Small Molecule Inhibitors Targeting Key Proteins in the DNA Damage Response for Cancer Therapy

doi:10.2174/0929867327666200224102309
摘要

DNA损伤反应(DDR)是一种复杂的相互作用途径。DDR通路的次级通路中出现的缺陷可能导致基因组不稳定和癌症易感性。DDR中某些蛋白的异常表达，特别是DNA修复通路中的异常表达，与癌细胞的生存和抵抗有关。因此，开发靶向DDR通路主要蛋白的小分子抑制剂是一种有效的癌症治疗策略。本文就靶向DDR通路主要蛋白的小分子抑制剂的研究进展作一综述，重点介绍其在癌症治疗中的应用。我们介绍了DDR分子抑制剂在临床前研究和肿瘤临床治疗中的作用模式，包括单药治疗、与化疗药物联合治疗或检查点抑制治疗。
关键词: DNA损伤反应(DDR)， DNA修复，小分子抑制剂，癌症治疗，单药治疗，联合治疗，合成致命(SL)，药物再利用
« Previous
[1] 
Purchase, I.F. Current knowledge of mechanisms of carcinogenicity: genotoxins versus non-genotoxins. Hum. Exp. Toxicol.,  1994, 13(1), 17-28.
[http://dx.doi.org/10.1177/096032719401300104] [PMID: 8198825] 
[2] 
Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature,  2009, 461(7267), 1071-1078.
[http://dx.doi.org/10.1038/nature08467] [PMID: 19847258] 
[3] 
Houtgraaf, J.H.; Versmissen, J.; van der Giessen, W.J. A concise review of DNA damage checkpoints and repair in mammalian cells. Cardiovasc. Revasc. Med.,  2006, 7(3), 165-172.
[http://dx.doi.org/10.1016/j.carrev.2006.02.002] [PMID: 16945824] 
[4] 
Sancar, A.; Lindsey-Boltz, L.A.; Unsal-Kaçmaz, K.; Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem.,  2004, 73, 39-85.
[http://dx.doi.org/10.1146/annurev.biochem.73.011303.073723] [PMID: 15189136] 
[5] 
Zhou, B.B.; Elledge, S.J. The DNA damage response: putting checkpoints in perspective. Nature,  2000, 408(6811), 433-439.
[http://dx.doi.org/10.1038/35044005] [PMID: 11100718] 
[6] 
Roos, W.P.; Kaina, B. DNA damage-induced cell death by apoptosis. Trends Mol. Med.,  2006, 12(9), 440-450.
[http://dx.doi.org/10.1016/j.molmed.2006.07.007] [PMID: 16899408] 
[7] 
Shibata, Y.; Morimoto, R.I. How the nucleus copes with proteotoxic stress? Curr. Biol.,  2014, 24(10), R463-R474.
[http://dx.doi.org/10.1016/j.cub.2014.03.033] [PMID: 24845679] 
[8] 
Powers, E.T.; Morimoto, R.I.; Dillin, A.; Kelly, J.W.; Balch, W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem.,  2009, 78, 959-991.
[http://dx.doi.org/10.1146/annurev.biochem.052308.114844] [PMID: 19298183] 
[9] 
Jeggo, P.A.; Pearl, L.H.; Carr, A.M. DNA repair, genome stability and cancer: a historical perspective. Nat. Rev. Cancer,  2016, 16(1), 35-42.
[http://dx.doi.org/10.1038/nrc.2015.4] [PMID: 26667849] 
[10] 
O’Connor, M.J. Targeting the DNA Damage Response in Cancer. Mol. Cell,  2015, 60(4), 547-560.
[http://dx.doi.org/10.1016/j.molcel.2015.10.040] [PMID: 26590714] 
[11] 
Hoeijmakers, J.H. DNA damage, aging, and cancer. N. Engl. J. Med.,  2009, 361(15), 1475-1485.
[http://dx.doi.org/10.1056/NEJMra0804615] [PMID: 19812404] 
[12] 
Lord, C.J.; Ashworth, A. The DNA damage response and cancer therapy. Nature,  2012, 481(7381), 287-294.
[http://dx.doi.org/10.1038/nature10760] [PMID: 22258607] 
[13] 
Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; Martin, N.M.; Jackson, S.P.; Smith, G.C.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature,  2005, 434(7035), 917-921.
[http://dx.doi.org/10.1038/nature03445] [PMID: 15829967] 
[14] 
Lord, C.J.; Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science,  2017, 355(6330), 1152-1158.
[http://dx.doi.org/10.1126/science.aam7344] [PMID: 28302823] 
[15] 
Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.O.; Hochhauser, D.; Arnold, D.; Oh, D.Y.; Reinacher-Schick, A.; Tortora, G.; Algül, H.; O’Reilly, E.M.; McGuinness, D.; Cui, K.Y.; Schlienger, K.; Locker, G.Y.; Kindler, H.L. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med.,  2019, 381(4), 317-327.
[http://dx.doi.org/10.1056/NEJMoa1903387] [PMID: 31157963] 
[16] 
Wang, M.; Li, E.; Lin, L.; Kumar, A.K.; Pan, F.; He, L.; Zhang, J.; Hu, Z.; Guo, Z. Enhanced activity of variant DNA Polymerase β (D160G) contributes to cisplatin therapy by impeding the efficiency of NER. Mol. Cancer Res.,  2019, 17(10), 2077-2088.
[http://dx.doi.org/10.1158/1541-7786.MCR-19-0482] [PMID: 31350308] 
[17] 
Nikolova, T.; Christmann, M.; Kaina, B. FEN1 is overexpressed in testis, lung and brain tumors. Anticancer Res.,  2009, 29(7), 2453-2459.
[PMID: 19596913] 
[18] 
Maacke, H.; Jost, K.; Opitz, S.; Miska, S.; Yuan, Y.; Hasselbach, L.; Lüttges, J.; Kalthoff, H.; Stürzbecher, H.W. DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma. Oncogene,  2000, 19(23), 2791-2795.
[http://dx.doi.org/10.1038/sj.onc.1203578] [PMID: 10851081] 
[19] 
He, L.; Luo, L.; Zhu, H.; Yang, H.; Zhang, Y.; Wu, H.; Sun, H.; Jiang, F.; Kathera, C.S.; Liu, L.; Zhuang, Z.; Chen, H.; Pan, F.; Hu, Z.; Zhang, J.; Guo, Z. FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer. Mol. Oncol.,  2017, 11(6), 640-654.
[http://dx.doi.org/10.1002/1878-0261.12058] [PMID: 28371273] 
[20] 
Foote, K.M.; Nissink, J.W.M.; McGuire, T.; Turner, P.; Guichard, S.; Yates, J.W.T.; Lau, A.; Blades, K.; Heathcote, D.; Odedra, R.; Wilkinson, G.; Wilson, Z.; Wood, C.M.; Jewsbury, P.J. Discovery and characterization of AZD6738, a potent inhibitor of Ataxia telangiectasia mutated and Rad3 related (ATR) kinase with application as an anticancer agent. J. Med. Chem.,  2018, 61(22), 9889-9907.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01187] [PMID: 30346772] 
[21] 
Eom, Y.W.; Kim, M.A.; Park, S.S.; Goo, M.J.; Kwon, H.J.; Sohn, S.; Kim, W.H.; Yoon, G.; Choi, K.S. Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene,  2005, 24(30), 4765-4777.
[http://dx.doi.org/10.1038/sj.onc.1208627] [PMID: 15870702] 
[22] 
Bang, Y.J.; Xu, R.H.; Chin, K.; Lee, K.W.; Park, S.H.; Rha, S.Y.; Shen, L.; Qin, S.; Xu, N.; Im, S.A.; Locker, G.; Rowe, P.; Shi, X.; Hodgson, D.; Liu, Y.Z.; Boku, N. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol.,  2017, 18(12), 1637-1651.
[http://dx.doi.org/10.1016/S1470-2045(17)30682-4] [PMID: 29103871] 
[23] 
Friedman, A.A.; Letai, A.; Fisher, D.E.; Flaherty, K.T. Precision medicine for cancer with next-generation functional diagnostics. Nat. Rev. Cancer,  2015, 15(12), 747-756.
[http://dx.doi.org/10.1038/nrc4015] [PMID: 26536825] 
[24] 
Dienstmann, R.; Vermeulen, L.; Guinney, J.; Kopetz, S.; Tejpar, S.; Tabernero, J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat. Rev. Cancer,  2017, 17(2), 79-92.
[http://dx.doi.org/10.1038/nrc.2016.126] [PMID: 28050011] 
[25] 
Politi, K.; Herbst, R.S. Lung cancer in the era of precision medicine. Clin. Cancer Res.,  2015, 21(10), 2213-2220.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2748] [PMID: 25979927] 
[26] 
Lyman, G.H.; Moses, H.L. Biomarker tests for molecularly targeted therapies--the key to unlocking precision medicine. N. Engl. J. Med.,  2016, 375(1), 4-6.
[http://dx.doi.org/10.1056/NEJMp1604033] [PMID: 27353537] 
[27] 
Tuli, R.; Shiao, S.L.; Nissen, N.; Tighiouart, M.; Kim, S.; Osipov, A.; Bryant, M.; Ristow, L.; Placencio-Hickok, V.; Hoffman, D.; Rokhsar, S.; Scher, K.; Klempner, S.J.; Noe, P.; Davis, M.J.; Wachsman, A.; Lo, S.; Jamil, L.; Sandler, H.; Piantadosi, S.; Hendifar, A. A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer. EBioMedicine,  2019, 40, 375-381.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.060] [PMID: 30635165] 
[28] 
Imai, K.; Takaoka, A. Comparing antibody and small-molecule therapies for cancer. Nat. Rev. Cancer,  2006, 6(9), 714-727.
[http://dx.doi.org/10.1038/nrc1913] [PMID: 16929325] 
[29] 
Lowndes, N.F.; Murguia, J.R. Sensing and responding to DNA damage. Curr. Opin. Genet. Dev.,  2000, 10(1), 17-25.
[http://dx.doi.org/10.1016/S0959-437X(99)00050-7] [PMID: 10679395] 
[30] 
Hickson, I.; Zhao, Y.; Richardson, C.J.; Green, S.J.; Martin, N.M.; Orr, A.I.; Reaper, P.M.; Jackson, S.P.; Curtin, N.J.; Smith, G.C. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res.,  2004, 64(24), 9152-9159.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2727] [PMID: 15604286] 
[31] 
Amé, J.C.; Spenlehauer, C.; de Murcia, G. The PARP superfamily. BioEssays,  2004, 26(8), 882-893.
[http://dx.doi.org/10.1002/bies.20085] [PMID: 15273990] 
[32] 
Morales, J.; Li, L.; Fattah, F.J.; Dong, Y.; Bey, E.A.; Patel, M.; Gao, J.; Boothman, D.A. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr.,  2014, 24(1), 15-28.
[http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2013006875] [PMID: 24579667] 
[33] 
Gavande, N.S.; VanderVere-Carozza, P.S.; Hinshaw, H.D.; Jalal, S.I.; Sears, C.R.; Pawelczak, K.S.; Turchi, J.J. DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol. Ther.,  2016, 160, 65-83.
[http://dx.doi.org/10.1016/j.pharmthera.2016.02.003] [PMID: 26896565] 
[34] 
Kummar, S.; Chen, A.; Parchment, R.E.; Kinders, R.J.; Ji, J.; Tomaszewski, J.E.; Doroshow, J.H. Advances in using PARP inhibitors to treat cancer. BMC Med.,  2012, 10, 25.
[http://dx.doi.org/10.1186/1741-7015-10-25] [PMID: 22401667] 
[35] 
Robert, I.; Dantzer, F.; Reina-San-Martin, B. Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. J. Exp. Med.,  2009, 206(5), 1047-1056.
[http://dx.doi.org/10.1084/jem.20082468] [PMID: 19364882] 
[36] 
Rodler, E.T.; Kurland, B.F.; Griffin, M.; Gralow, J.R.; Porter, P.; Yeh, R.F.; Gadi, V.K.; Guenthoer, J.; Beumer, J.H.; Korde, L.; Strychor, S.; Kiesel, B.F.; Linden, H.M.; Thompson, J.A.; Swisher, E.; Chai, X.; Shepherd, S.; Giranda, V.; Specht, J.M.; Phase, I.; Phase, I. Study of veliparib (ABT-888) combined with cisplatin and vinorelbine in advanced triple-negative breast cancer and/or BRCA mutation-associated breast cancer. Clin. Cancer Res.,  2016, 22(12), 2855-2864.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2137] [PMID: 26801247] 
[37] 
Moore, K.N.; Secord, A.A.; Geller, M.A.; Miller, D.S.; Cloven, N.; Fleming, G.F.; Wahner Hendrickson, A.E.; Azodi, M.; DiSilvestro, P.; Oza, A.M.; Cristea, M.; Berek, J.S.; Chan, J.K.; Rimel, B.J.; Matei, D.E.; Li, Y.; Sun, K.; Luptakova, K.; Matulonis, U.A.; Monk, B.J. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol.,  2019, 20(5), 636-648.
[http://dx.doi.org/10.1016/S1470-2045(19)30029-4] [PMID: 30948273] 
[38] 
Roviello, G.; Milani, M.; Gobbi, A.; Dester, M.; Cappelletti, M.R.; Allevi, G.; Aguggini, S.; Ravelli, A.; Gussago, F.; Cocconi, A.; Zanotti, L.; Senti, C.; Strina, C.; Bottini, A.; Generali, D. A Phase II study of olaparib in breast cancer patients: biological evaluation from a ‘window of opportunity’ trial. Future Oncol.,  2016, 12(19), 2189-2193.
[http://dx.doi.org/10.2217/fon-2016-0116] [PMID: 27324108] 
[39] 
Ettl, J.; Quek, R.G.W.; Lee, K.H.; Rugo, H.S.; Hurvitz, S.; Gonçalves, A.; Fehrenbacher, L.; Yerushalmi, R.; Mina, L.A.; Martin, M.; Roché, H.; Im, Y.H.; Markova, D.; Bhattacharyya, H.; Hannah, A.L.; Eiermann, W.; Blum, J.L.; Litton, J.K. Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann. Oncol.,  2018, 29(9), 1939-1947.
[http://dx.doi.org/10.1093/annonc/mdy257] [PMID: 30124753] 
[40] 
Shirley, M. Rucaparib: a review in ovarian cancer. Target. Oncol.,  2019, 14(2), 237-246.
[http://dx.doi.org/10.1007/s11523-019-00629-5] [PMID: 30830551] 
[41] 
Wilson, R.H.; Evans, T.J.; Middleton, M.R.; Molife, L.R.; Spicer, J.; Dieras, V.; Roxburgh, P.; Giordano, H.; Jaw-Tsai, S.; Goble, S.; Plummer, R. A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br. J. Cancer,  2017, 116(7), 884-892.
[http://dx.doi.org/10.1038/bjc.2017.36] [PMID: 28222073] 
[42] 
Turk, A.A.; Wisinski, K.B. PARP inhibitors in breast cancer: bringing synthetic lethality to the bedside. Cancer,  2018, 124(12), 2498-2506.
[http://dx.doi.org/10.1002/cncr.31307] [PMID: 29660759] 
[43] 
Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature,  2005, 434(7035), 913-917.
[http://dx.doi.org/10.1038/nature03443] [PMID: 15829966] 
[44] 
Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; Ashworth, A.; Carmichael, J.; Kaye, S.B.; Schellens, J.H.; de Bono, J.S. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med.,  2009, 361(2), 123-134.
[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] 
[45] 
Ashworth, A.; Lord, C.J.; Reis-Filho, J.S. Genetic interactions in cancer progression and treatment. Cell,  2011, 145(1), 30-38.
[http://dx.doi.org/10.1016/j.cell.2011.03.020] [PMID: 21458666] 
[46] 
Chan, D.A.; Giaccia, A.J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov.,  2011, 10(5), 351-364.
[http://dx.doi.org/10.1038/nrd3374] [PMID: 21532565] 
[47] 
Aly, A.; Ganesan, S. BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. J. Mol. Cell Biol.,  2011, 3(1), 66-74.
[http://dx.doi.org/10.1093/jmcb/mjq055] [PMID: 21278454] 
[48] 
Meghani, K.; Fuchs, W.; Detappe, A.; Drané, P.; Gogola, E.; Rottenberg, S.; Jonkers, J.; Matulonis, U.; Swisher, E.M.; Konstantinopoulos, P.A.; Chowdhury, D. Multifaceted impact of MicroRNA 493-5p on genome-stabilizing pathways induces platinum and PARP inhibitor resistance in BRCA2-mutated carcinomas. Cell Rep.,  2018, 23(1), 100-111.
[http://dx.doi.org/10.1016/j.celrep.2018.03.038] [PMID: 29617652] 
[49] 
Fukumoto, T.; Zhu, H.; Nacarelli, T.; Karakashev, S.; Fatkhutdinov, N.; Wu, S.; Liu, P.; Kossenkov, A.V.; Showe, L.C.; Jean, S.; Zhang, L.; Zhang, RN (6)-methylation of adenosine of FZD10 mRNA contributes to PARP inhibitor resistance. Cancer Res., 2019.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3592] [PMID: 30967398] 
[50] 
Lee, J.H.; Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science,  2005, 308(5721), 551-554.
[http://dx.doi.org/10.1126/science.1108297] [PMID: 15790808] 
[51] 
Bakkenist, C.J.; Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature,  2003, 421(6922), 499-506.
[http://dx.doi.org/10.1038/nature01368] [PMID: 12556884] 
[52] 
Scully, R.; Xie, A. Double strand break repair functions of histone H2AX. Mutat. Res.,  2013, 750(1-2), 5-14.
[http://dx.doi.org/10.1016/j.mrfmmm.2013.07.007] [PMID: 23916969] 
[53] 
Burma, S.; Chen, B.P.; Murphy, M.; Kurimasa, A.; Chen, D.J. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem.,  2001, 276(45), 42462-42467.
[http://dx.doi.org/10.1074/jbc.C100466200] [PMID: 11571274] 
[54] 
Falck, J.; Mailand, N.; Syljuåsen, R.G.; Bartek, J.; Lukas, J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature,  2001, 410(6830), 842-847.
[http://dx.doi.org/10.1038/35071124] [PMID: 11298456] 
[55] 
Barlow, C.; Brown, K.D.; Deng, C.X.; Tagle, D.A.; Wynshaw-Boris, A. ATM selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways. Nat. Genet.,  1997, 17(4), 453-456.
[http://dx.doi.org/10.1038/ng1297-453] [PMID: 9398849] 
[56] 
Cortez, D.; Wang, Y.; Qin, J.; Elledge, S.J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science,  1999, 286(5442), 1162-1166.
[http://dx.doi.org/10.1126/science.286.5442.1162] [PMID: 10550055] 
[57] 
Tribius, S.; Pidel, A.; Casper, D. ATM protein expression correlates with radioresistance in primary glioblastoma cells in culture. Int. J. Radiat. Oncol. Biol. Phys.,  2001, 50(2), 511-523.
[http://dx.doi.org/10.1016/S0360-3016(01)01489-4] [PMID: 11380241] 
[58] 
Weber, A.M.; Ryan, A.J. ATM and ATR as therapeutic targets in cancer. Pharmacol. Ther.,  2015, 149, 124-138.
[http://dx.doi.org/10.1016/j.pharmthera.2014.12.001] [PMID: 25512053] 
[59] 
Barlaam, B.; Pike, K. Identifying high quality, potent and selective inhibitors of ATM kinase: discovery of AZD0156. Eur. J. Cancer,  2016, 61, S118-S118.
[http://dx.doi.org/10.1016/S0959-8049(16)61417-X] 
[60] 
Pike, K.G.; Barlaam, B.; Cadogan, E.; Campbell, A.; Chen, Y.; Colclough, N.; Davies, N.L.; de-Almeida, C.; Degorce, S.L.; Didelot, M.; Dishington, A.; Ducray, R.; Durant, S.T.; Hassall, L.A.; Holmes, J.; Hughes, G.D.; MacFaul, P.A.; Mulholland, K.R.; McGuire, T.M.; Ouvry, G.; Pass, M.; Robb, G.; Stratton, N.; Wang, Z.; Wilson, J.; Zhai, B.; Zhao, K.; Al-Huniti, N. The identification of potent, selective, and orally available inhibitors of ataxia telangiectasia mutated (ATM) kinase: The discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one). J. Med. Chem.,  2018, 61(9), 3823-3841.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01896] [PMID: 29683659] 
[61] 
Pike, K.G.J.C.M.C.I. 8.07 – Discovery of AZD0156: The First Potent and Selective Inhibitor of ATM Kinase for Clinical Evaluation., 2017.
[http://dx.doi.org/10.1016/B978-0-12-409547-2.13801-6] 
[62] 
Karlin, J.; Allen, J.; Ahmad, S.F.; Hughes, G.; Sheridan, V.; Odedra, R.; Farrington, P.; Cadogan, E.B.; Riches, L.C.; Garcia-Trinidad, A.; Thomason, A.G.; Patel, B.; Vincent, J.; Lau, A.; Pike, K.G.; Hunt, T.A.; Sule, A.; Valerie, N.C.K.; Biddlestone-Thorpe, L.; Kahn, J.; Beckta, J.M.; Mukhopadhyay, N.; Barlaam, B.; Degorce, S.L.; Kettle, J.; Colclough, N.; Wilson, J.; Smith, A.; Barrett, I.P.; Zheng, L.; Zhang, T.; Wang, Y.; Chen, K.; Pass, M.; Durant, S.T.; Valerie, K. Orally bioavailable and blood-brain barrier-penetrating ATM inhibitor (AZ32) radiosensitizes intracranial gliomas in mice. Mol. Cancer Ther.,  2018, 17(8), 1637-1647.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0975] [PMID: 29769307] 
[63] 
Fuchss, T.; Mederski, W.W.; Zenke, F.T.; Dahmen, H.; Zimmermann, A.; Blaukat, A. Highly potent and selective ATM kinase inhibitor M3541: A clinical candidate drug with strong antitumor activity in combination with radiotherapy. Cancer Res.,  2018, 78(13)
[http://dx.doi.org/10.1158/1538-7445.AM2018-329] 
[64] 
Shiloh, Y. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev.,  2001, 11(1), 71-77.
[http://dx.doi.org/10.1016/S0959-437X(00)00159-3] [PMID: 11163154] 
[65] 
Ammazzalorso, F.; Pirzio, L.M.; Bignami, M.; Franchitto, A.; Pichierri, P. ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J.,  2010, 29(18), 3156-3169.
[http://dx.doi.org/10.1038/emboj.2010.205] [PMID: 20802463] 
[66] 
Smith, J.; Tho, L.M.; Xu, N.H.; Gillespie, D.A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Advan. Cancer Res.,  2010, 108, 73-112.
[http://dx.doi.org/10.1016/B978-0-12-380888-2.00003-0] 
[67] 
Schoppy, D.W.; Ragland, R.L.; Gilad, O.; Shastri, N.; Peters, A.A.; Murga, M.; Fernandez-Capetillo, O.; Diehl, J.A.; Brown, E.J. Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J. Clin. Invest.,  2012, 122(1), 241-252.
[http://dx.doi.org/10.1172/JCI58928] [PMID: 22133876] 
[68] 
He, G.; Siddik, Z.H.; Huang, Z.; Wang, R.; Koomen, J.; Kobayashi, R.; Khokhar, A.R.; Kuang, J. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene,  2005, 24(18), 2929-2943.
[http://dx.doi.org/10.1038/sj.onc.1208474] [PMID: 15735718] 
[69] 
Taylor, W.R.; Stark, G.R. Regulation of the G2/M transition by p53. Oncogene,  2001, 20(15), 1803-1815.
[http://dx.doi.org/10.1038/sj.onc.1204252] [PMID: 11313928] 
[70] 
Fokas, E.; Prevo, R.; Pollard, J.R.; Reaper, P.M.; Charlton, P.A.; Cornelissen, B.; Vallis, K.A.; Hammond, E.M.; Olcina, M.M.; Gillies McKenna, W.; Muschel, R.J.; Brunner, T.B. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis.,  2012, 3e441
[http://dx.doi.org/10.1038/cddis.2012.181] [PMID: 23222511] 
[71] 
Foote, K.M.; Blades, K.; Cronin, A.; Fillery, S.; Guichard, S.S.; Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P.J.; McGuire, T.M.; Nissink, J.W.; Odedra, R.; Page, K.; Perkins, P.; Suleman, A.; Tam, K.; Thommes, P.; Broadhurst, R.; Wood, C. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J. Med. Chem.,  2013, 56(5), 2125-2138.
[http://dx.doi.org/10.1021/jm301859s] [PMID: 23394205] 
[72] 
Mei, L.; Zhang, J.; He, K.; Zhang, J. Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand. J. Hematol. Oncol.,  2019, 12(1), 43.
[http://dx.doi.org/10.1186/s13045-019-0733-6] [PMID: 31018854] 
[73] 
Yoshida, G.J. Emerging roles of Myc in stem cell biology and novel tumor therapies. J. Exp. Clin. Cancer Res.,  2018, 37(1), 173.
[http://dx.doi.org/10.1186/s13046-018-0835-y] [PMID: 30053872] 
[74] 
Wengner, A.M.; Siemeister, G.; Luecking, U.; Lefranc, J.; Lienau, P.; Deeg, G.; Lagkadinou, E.; Liu, L.; Golfier, S.; Schatz, C.; Scholz, A.; von Nussbaum, F.; Brands, M.; Mumberg, D.; Ziegelbauer, K. ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models. Cancer Res.,  2017, 77(13), 836.
[http://dx.doi.org/10.1158/1538-7445.AM2017-836] 
[75] 
Uto, K.; Inoue, D.; Shimuta, K.; Nakajo, N.; Sagata, N. Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism. EMBO J.,  2004, 23(16), 3386-3396.
[http://dx.doi.org/10.1038/sj.emboj.7600328] [PMID: 15272308] 
[76] 
Rundle, S.; Bradbury, A.; Drew, Y.; Curtin, N.J. Targeting the ATR-CHK1 axis in cancer therapy. Cancers (Basel),  2017, 9(5)E41
[http://dx.doi.org/10.3390/cancers9050041] [PMID: 28448462] 
[77] 
Italiano, A.; Infante, J.R.; Shapiro, G.I.; Moore, K.N.; LoRusso, P.M.; Hamilton, E.; Cousin, S.; Toulmonde, M.; Postel-Vinay, S.; Tolaney, S.; Blackwood, E.M.; Mahrus, S.; Peale, F.V.; Lu, X.; Moein, A.; Epler, J.; DuPree, K.; Tagen, M.; Murray, E.R.; Schutzman, J.L.; Lauchle, J.O.; Hollebecque, A.; Soria, J.C. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann. Oncol.,  2018, 29(5), 1304-1311.
[http://dx.doi.org/10.1093/annonc/mdy076] [PMID: 29788155] 
[78] 
King, C.; Diaz, H.B.; McNeely, S.; Barnard, D.; Dempsey, J.; Blosser, W.; Beckmann, R.; Barda, D.; Marshall, M.S. LY2606368 causes replication catastrophe and antitumor effects through CHK1-dependent mechanisms. Mol. Cancer Ther.,  2015, 14(9), 2004-2013.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-1037] [PMID: 26141948] 
[79] 
Hong, D.; Infante, J.; Janku, F.; Jones, S.; Nguyen, L.M.; Burris, H.; Naing, A.; Bauer, T.M.; Piha-Paul, S.; Johnson, F.M.; Kurzrock, R.; Golden, L.; Hynes, S.; Lin, J.; Lin, A.B.; Bendell, J.; Phase, I. Phase I study of LY2606368, a checkpoint kinase 1 inhibitor, in patients with advanced cancer. J. Clin. Oncol.,  2016, 34(15), 1764-1771.
[http://dx.doi.org/10.1200/JCO.2015.64.5788] [PMID: 27044938] 
[80] 
Calvo, E.; Braiteh, F.; Von Hoff, D.; McWilliams, R.; Becerra, C.; Galsky, M.D.; Jameson, G.; Lin, J.; McKane, S.; Wickremsinhe, E.R.; Hynes, S.M.; Bence; Lin,  A.; Hurt, K.; Richards, D. Phase I study of CHK1 inhibitor LY2603618 in combination with gemcitabine in patients with solid tumors. Oncology,  2016, 91(5), 251-260.
[http://dx.doi.org/10.1159/000448621] [PMID: 27598338] 
[81] 
Scagliotti, G.; Kang, J.H.; Smith, D.; Rosenberg, R.; Park, K.; Kim, S.W.; Su, W.C.; Boyd, T.E.; Richards, D.A.; Novello, S.; Hynes, S.M.; Myrand, S.P.; Lin, J.; Smyth, E.N.; Wijayawardana, S.; Lin, A.B.; Pinder-Schenck, M. Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Invest. New Drugs,  2016, 34(5), 625-635.
[http://dx.doi.org/10.1007/s10637-016-0368-1] [PMID: 27350064] 
[82] 
Booth, L.; Roberts, J.; Poklepovic, A.; Dent, P. The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells. Cancer Biol. Ther.,  2018, 19(9), 786-796.
[http://dx.doi.org/10.1080/15384047.2018.1472189] [PMID: 30024813] 
[83] 
Dent, P. Investigational CHK1 inhibitors in early phase clinical trials for the treatment of cancer. Expert Opin. Investig. Drugs,  2019, 28(12), 1095-1100.
[http://dx.doi.org/10.1080/13543784.2019.1694661] [PMID: 31783714] 
[84] 
Chenard-Poirier, M.; Garces, A.H.I.; Jones, R.H.; Quinton, A.; Plummer, E.R.; Drew, Y.; Kowalski, M.M.; Klencke, B.J.; Banerji, U. A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer. J. Clin. Oncol.,  2017, TPS2607-TPS2607.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.TPS2607] 
[85] 
Aparicio, T.; Baer, R.; Gautier, J. DNA double-strand break repair pathway choice and cancer. DNA Repair (Amst.),  2014, 19, 169-175.
[http://dx.doi.org/10.1016/j.dnarep.2014.03.014] [PMID: 24746645] 
[86] 
Kakarougkas, A.; Jeggo, P.A. DNA DSB repair pathway choice: an orchestrated handover mechanism. Br. J. Radiol.,  2014, 87(1035)20130685
[http://dx.doi.org/10.1259/bjr.20130685] [PMID: 24363387] 
[87] 
Memisoglu, A.; Samson, L. Base excision repair in yeast and mammals. Mutat. Res.,  2000, 451(1-2), 39-51.
[http://dx.doi.org/10.1016/S0027-5107(00)00039-7] [PMID: 10915864] 
[88] 
Li, W.; Liu, W.; Kakoki, A.; Wang, R.; Adebali, O.; Jiang, Y.; Sancar, A. Nucleotide excision repair capacity increases during differentiation of human embryonic carcinoma cells into neurons and muscle cells. J. Biol. Chem.,  2019, 294(15), 5914-5922.
[http://dx.doi.org/10.1074/jbc.RA119.007861] [PMID: 30808711] 
[89] 
Khanna, K.K.; Jackson, S.P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat. Genet.,  2001, 27(3), 247-254.
[http://dx.doi.org/10.1038/85798] [PMID: 11242102] 
[90] 
Li, X.; Heyer, W.D. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res.,  2008, 18(1), 99-113.
[http://dx.doi.org/10.1038/cr.2008.1] [PMID: 18166982] 
[91] 
San Filippo, J.; Sung, P.; Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem.,  2008, 77, 229-257.
[http://dx.doi.org/10.1146/annurev.biochem.77.061306.125255] [PMID: 18275380] 
[92] 
Budke, B.; Tueckmantel, W.; Miles, K.; Kozikowski, A.P.; Connell, P.P. Optimization of drug candidates that inhibit the D-Loop activity of RAD51. ChemMedChem,  2019, 14(10), 1031-1040.
[http://dx.doi.org/10.1002/cmdc.201900075] [PMID: 30957434] 
[93] 
Takaku, M.; Kainuma, T.; Ishida-Takaku, T.; Ishigami, S.; Suzuki, H.; Tashiro, S.; van Soest, R.W.; Nakao, Y.; Kurumizaka, H. Halenaquinone, a chemical compound that specifically inhibits the secondary DNA binding of RAD51. Genes Cells,  2011, 16(4), 427-436.
[http://dx.doi.org/10.1111/j.1365-2443.2011.01494.x] [PMID: 21375680] 
[94] 
Richardson, C. RAD51, genomic stability, and tumorigenesis. Cancer Lett.,  2005, 218(2), 127-139.
[http://dx.doi.org/10.1016/j.canlet.2004.08.009] [PMID: 15670890] 
[95] 
Adam-Zahir, S.; Plowman, P.N.; Bourton, E.C.; Sharif, F.; Parris, C.N. Increased γ-H2AX and Rad51 DNA repair biomarker expression in human cell lines resistant to the chemotherapeutic agents nitrogen mustard and cisplatin. Chemotherapy,  2014, 60(5-6), 310-320.
[http://dx.doi.org/10.1159/000430086] [PMID: 26138778] 
[96] 
Huang, F.; Mazin, A.V. A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts. PLoS One,  2014, 9(6)e100993
[http://dx.doi.org/10.1371/journal.pone.0100993] [PMID: 24971740] 
[97] 
Budke, B.; Logan, H.L.; Kalin, J.H.; Zelivianskaia, A.S.; Cameron McGuire, W.; Miller, L.L.; Stark, J.M.; Kozikowski, A.P.; Bishop, D.K.; Connell, P.P. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res.,  2012, 40(15), 7347-7357.
[http://dx.doi.org/10.1093/nar/gks353] [PMID: 22573178] 
[98] 
Ishida, T.; Takizawa, Y.; Kainuma, T.; Inoue, J.; Mikawa, T.; Shibata, T.; Suzuki, H.; Tashiro, S.; Kurumizaka, H. DIDS, a chemical compound that inhibits RAD51-mediated homologous pairing and strand exchange. Nucleic Acids Res.,  2009, 37(10), 3367-3376.
[http://dx.doi.org/10.1093/nar/gkp200] [PMID: 19336413] 
[99] 
Budke, B.; Lv, W.; Kozikowski, A.P.; Connell, P.P. Recent developments using small molecules to target RAD51: how to best modulate RAD51 for anticancer therapy? ChemMedChem,  2016, 11(22), 2468-2473.
[http://dx.doi.org/10.1002/cmdc.201600426] [PMID: 27781374] 
[100] 
Normand, A.; Rivière, E.; Renodon-Cornière, A. Identification and characterization of human Rad51 inhibitors by screening of an existing drug library. Biochem. Pharmacol.,  2014, 91(3), 293-300.
[http://dx.doi.org/10.1016/j.bcp.2014.07.033] [PMID: 25124703] 
[101] 
Burma, S.; Chen, B.P.; Chen, D.J. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst.),  2006, 5(9-10), 1042-1048.
[http://dx.doi.org/10.1016/j.dnarep.2006.05.026] [PMID: 16822724] 
[102] 
Ceccaldi, R.; Rondinelli, B.; D’Andrea, A.D. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol.,  2016, 26(1), 52-64.
[http://dx.doi.org/10.1016/j.tcb.2015.07.009] [PMID: 26437586] 
[103] 
Nick McElhinny, S.A.; Havener, J.M.; Garcia-Diaz, M.; Juárez, R.; Bebenek, K.; Kee, B.L.; Blanco, L.; Kunkel, T.A.; Ramsden, D.A. A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol. Cell,  2005, 19(3), 357-366.
[http://dx.doi.org/10.1016/j.molcel.2005.06.012] [PMID: 16061182] 
[104] 
Ahnesorg, P.; Smith, P.; Jackson, S.P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell,  2006, 124(2), 301-313.
[http://dx.doi.org/10.1016/j.cell.2005.12.031] [PMID: 16439205] 
[105] 
Beskow, C.; Skikuniene, J.; Holgersson, A.; Nilsson, B.; Lewensohn, R.; Kanter, L.; Viktorsson, K. Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86. Br. J. Cancer,  2009, 101(5), 816-821.
[http://dx.doi.org/10.1038/sj.bjc.6605201] [PMID: 19672258] 
[106] 
Munster, P.N.; Mahipal, A.; Nemunaitis, J.J.; Mita, M.M.; Paz-Ares, L.G.; Massard, C.; Mikkelsen, T.; Cruz, C.; Rathkopf, D.E.; Blumenschein, G.R.; Hidalgo, M.; Smith, D.C.; Eichhorst, B.; Cloughesy, T.F.; Garrick, B.; Trowe, T.; Filvaroff, E.; Hege, K.; Bendell, J.C. Phase I trial of a dual TOR kinase and DNA-PK inhibitor (CC-115) in advanced solid and hematologic cancers. J. Clin. Oncol.,  2016, 34(15), 2505-2505.
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.2505] 
[107] 
Mortensen, D.S.; Perrin-Ninkovic, S.M.; Shevlin, G.; Elsner, J.; Zhao, J.; Whitefield, B.; Tehrani, L.; Sapienza, J.; Riggs, J.R.; Parnes, J.S.; Papa, P.; Packard, G.; Lee, B.G.; Harris, R.; Correa, M.; Bahmanyar, S.; Richardson, S.J.; Peng, S.X.; Leisten, J.; Khambatta, G.; Hickman, M.; Gamez, J.C.; Bisonette, R.R.; Apuy, J.; Cathers, B.E.; Canan, S.S.; Moghaddam, M.F.; Raymon, H.K.; Worland, P.; Narla, R.K.; Fultz, K.E.; Sankar, S. Optimization of a series of triazole containing mammalian target of rapamycin (Mtor) kinase inhibitors and the discovery of CC-115. J. Med. Chem.,  2015, 58(14), 5599-5608.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00627] [PMID: 26102506] 
[108] 
Damstrup, L.; Zimmerman, A.; Sirrenberg, C.; Zenke, F.; Vassilev, L. M3814, a DNA-dependent protein kinase inhibitor (DNA-PKi), potentiates the effect of ionizing radiation (IR) in xenotransplanted tumors in nude mice. Int. J. Radiat. Oncol. Biol. Phys.,  2016, 94(4), 940-941.
[http://dx.doi.org/10.1016/j.ijrobp.2015.12.268] 
[109] 
van Bussel, M.; Mau-Soerensen, M.; Damstrup, L.; Nielsen, D.; Verheul, H.M.W.; Aftimos, P.G.; De Jonge, M.J.; Berghoff, K.; Schellens, J.H.M. A multicenter phase I trial of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814 in patients with solid tumors. J. Clin. Oncol.,  2017, 2556.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.2556] 
[110] 
Timme, C.R.; Rath, B.H.; O’Neill, J.W.; Camphausen, K.; Tofilon, P.J. The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. Mol. Cancer Ther.,  2018, 17(6), 1207-1216.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-1267] [PMID: 29549168] 
[111] 
Boucher, D.; Newsome, D.; Takemoto, D.; Hillier, S.; Wang, Y.; Arimoto, R.; Maxwell, J.; Charifson, P.; Fields, S.Z.; Tanner, K.; Penney, M.S. Preclinical characterization of VX-984, a selective DNA-dependent protein kinase (DNA-PK) inhibitor in combination with doxorubicin in breast and ovarian cancers. Cancer Res.,  2017, 77.
[http://dx.doi.org/10.1158/1538-7445.SABCS16-P5-06-05] 
[112] 
Fu, D.; Calvo, J.A.; Samson, L.D. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer,  2012, 12(2), 104-120.
[http://dx.doi.org/10.1038/nrc3185] [PMID: 22237395] 
[113] 
David, S.S.; O’Shea, V.L.; Kundu, S. Base-excision repair of oxidative DNA damage. Nature,  2007, 447(7147), 941-950.
[http://dx.doi.org/10.1038/nature05978] [PMID: 17581577] 
[114] 
Fortini, P.; Pascucci, B.; Parlanti, E.; D’Errico, M.; Simonelli, V.; Dogliotti, E. The base excision repair: mechanisms and its relevance for cancer susceptibility. Biochimie,  2003, 85(11), 1053-1071.
[http://dx.doi.org/10.1016/j.biochi.2003.11.003] [PMID: 14726013] 
[115] 
Zharkov, D.O.; Grollman, A.P. The DNA trackwalkers: principles of lesion search and recognition by DNA glycosylases. Mutat. Res.,  2005, 577(1-2), 24-54.
[http://dx.doi.org/10.1016/j.mrfmmm.2005.03.011] [PMID: 15939442] 
[116] 
Prasad, R.; Dianov, G.L.; Bohr, V.A.; Wilson, S.H. FEN1 stimulation of DNA polymerase beta mediates an excision step in mammalian long patch base excision repair. J. Biol. Chem.,  2000, 275(6), 4460-4466.
[http://dx.doi.org/10.1074/jbc.275.6.4460] [PMID: 10660619] 
[117] 
Hosfield, D.J.; Mol, C.D.; Shen, B.; Tainer, J.A. Structure of the DNA repair and replication endonuclease and exonuclease FEN-1: coupling DNA and PCNA binding to FEN-1 activity. Cell,  1998, 95(1), 135-146.
[http://dx.doi.org/10.1016/S0092-8674(00)81789-4] [PMID: 9778254] 
[118] 
Chapados, B.R.; Hosfield, D.J.; Han, S.; Qiu, J.; Yelent, B.; Shen, B.; Tainer, J.A. Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair. Cell,  2004, 116(1), 39-50.
[http://dx.doi.org/10.1016/S0092-8674(03)01036-5] [PMID: 14718165] 
[119] 
He, L.; Zhang, Y.; Sun, H.; Jiang, F.; Yang, H.; Wu, H.; Zhou, T.; Hu, S.; Kathera, C.S.; Wang, X.; Chen, H.; Li, H.; Shen, B.; Zhu, Y.; Guo, Z. Targeting DNA flap endonuclease 1 to impede breast cancer progression. EBioMedicine,  2016, 14, 32-43.
[http://dx.doi.org/10.1016/j.ebiom.2016.11.012] [PMID: 27852524] 
[120] 
Singh, P.; Yang, M.; Dai, H.; Yu, D.; Huang, Q.; Tan, W.; Kernstine, K.H.; Lin, D.; Shen, B. Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers. Mol. Cancer Res.,  2008, 6(11), 1710-1717.
[http://dx.doi.org/10.1158/1541-7786.MCR-08-0269] [PMID: 19010819] 
[121] 
Lam, J.S.; Seligson, D.B.; Yu, H.; Li, A.; Eeva, M.; Pantuck, A.J.; Zeng, G.; Horvath, S.; Belldegrun, A.S. Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score. BJU Int.,  2006, 98(2), 445-451.
[http://dx.doi.org/10.1111/j.1464-410X.2006.06224.x] [PMID: 16879693] 
[122] 
Lu, X.; Liu, R.; Wang, M.; Kumar, A.K.; Pan, F.; He, L.; Hu, Z.; Guo, Z. MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene,  2020, 39(1), 234-247.
[http://dx.doi.org/10.1038/s41388-019-0986-0] [PMID: 31471584] 
[123] 
Exell, J.C.; Thompson, M.J.; Finger, L.D.; Shaw, S.J.; Debreczeni, J.; Ward, T.A.; McWhirter, C.; Siöberg, C.L.B.; Martinez Molina, D.; Abbott, W.M.; Jones, C.D.; Nissink, J.W.M.; Durant, S.T.; Grasby, J.A. Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nat. Chem. Biol.,  2016, 12(10), 815-821.
[http://dx.doi.org/10.1038/nchembio.2148] [PMID: 27526030] 
[124] 
Panda, H.; Jaiswal, A.S.; Corsino, P.E.; Armas, M.L.; Law, B.K.; Narayan, S. Amino acid Asp181 of 5′-flap endonuclease 1 is a useful target for chemotherapeutic development. Biochemistry,  2009, 48(42), 9952-9958.
[http://dx.doi.org/10.1021/bi9010754] [PMID: 19769410] 
[125] 
He, L.; Yang, H.; Zhou, S.; Zhu, H.; Mao, H.; Ma, Z.; Wu, T.; Kumar, A.K.; Kathera, C.; Janardhan, A.; Pan, F.; Hu, Z.; Yang, Y.; Luo, L.; Guo, Z. Synergistic antitumor effect of combined paclitaxel with FEN1 inhibitor in cervical cancer cells. DNA Repair (Amst.),  2018, 63, 1-9.
[http://dx.doi.org/10.1016/j.dnarep.2018.01.003] [PMID: 29358095] 
[126] 
van Pel, D.M.; Barrett, I.J.; Shimizu, Y.; Sajesh, B.V.; Guppy, B.J.; Pfeifer, T.; McManus, K.J.; Hieter, P. An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development. PLoS Genet.,  2013, 9(1)e1003254
[http://dx.doi.org/10.1371/journal.pgen.1003254] [PMID: 23382697] 
[127] 
Demple, B.; Sung, J.S. Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair (Amst.),  2005, 4(12), 1442-1449.
[http://dx.doi.org/10.1016/j.dnarep.2005.09.004] [PMID: 16199212] 
[128] 
Marenstein, D.R.; Wilson, D.M., III; Teebor, G.W. Human AP endonuclease (APE1) demonstrates endonucleolytic activity against AP sites in single-stranded DNA. DNA Repair (Amst.),  2004, 3(5), 527-533.
[http://dx.doi.org/10.1016/j.dnarep.2004.01.010] [PMID: 15084314] 
[129] 
Bobola, M.S.; Finn, L.S.; Ellenbogen, R.G.; Geyer, J.R.; Berger, M.S.; Braga, J.M.; Meade, E.H.; Gross, M.E.; Silber, J.R. Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy in medulloblastoma and primitive neuroectodermal tumors. Clin. Cancer Res.,  2005, 11(20), 7405-7414.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1068] [PMID: 16243814] 
[130] 
Silber, J.R.; Bobola, M.S.; Blank, A.; Schoeler, K.D.; Haroldson, P.D.; Huynh, M.B.; Kolstoe, D.D. The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. Clin. Cancer Res.,  2002, 8(9), 3008-3018.
[PMID: 12231548] 
[131] 
Kumar, K.; Jackson, J.L.; Kelley, M.R.; Ivan, M.; Sandsuky, G. Significant in vivo activity of an APE1/Ref-1 redox inhibitor, E3330, alone and in combination with Bevacizumab in a glioblastoma mouse model analyzed by a whole slide digital imaging system and quantitative immunohistochemistry. Cancer Res.,  2012, 1769.
[http://dx.doi.org/10.1158/1538-7445.AM2012-1769] 
[132] 
Madhusudan, S.; Smart, F.; Shrimpton, P.; Parsons, J.L.; Gardiner, L.; Houlbrook, S.; Talbot, D.C.; Hammonds, T.; Freemont, P.A.; Sternberg, M.J.; Dianov, G.L.; Hickson, I.D. Isolation of a small molecule inhibitor of DNA base excision repair. Nucleic Acids Res.,  2005, 33(15), 4711-4724.
[http://dx.doi.org/10.1093/nar/gki781] [PMID: 16113242] 
[133] 
Qian, C.; Li, M.; Sui, J.; Ren, T.; Li, Z.; Zhang, L.; Zhou, L.; Cheng, Y.; Wang, D. Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor. Drug Des. Devel. Ther.,  2014, 8, 485-496.
[http://dx.doi.org/10.2147/DDDT.S62963] [PMID: 24872679] 
[134] 
Ren, T.; Shan, J.; Li, M.; Qing, Y.; Qian, C.; Wang, G.; Li, Q.; Lu, G.; Li, C.; Peng, Y.; Luo, H.; Zhang, S.; Yang, Y.; Cheng, Y.; Wang, D.; Zhou, S.F. Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer. Drug Des. Devel. Ther.,  2015, 9, 2887-2910.
[http://dx.doi.org/10.2147/DDDT.S82724] [PMID: 26089640] 
[135] 
Abbotts, R.M.; Sultana, R.; Seedhouse, C.; Patel, P.M.; Wilson, D.M.; Madhusudan, S. Synthetic lethal targeting of PTEN-associated homologous recombination (HR) deficient melanoma cells by human apurinic/apyrimidinic endonuclease (APE1) inhibitors. Cancer Res.,  2012, 72, 615.
[http://dx.doi.org/10.1158/1538-7445.AM2012-LB-263] 
[136] 
Ménézo, Y.; Dale, B.; Cohen, M. DNA damage and repair in human oocytes and embryos: a review. Zygote,  2010, 18(4), 357-365.
[http://dx.doi.org/10.1017/S0967199410000286] [PMID: 20663262] 
[137] 
Marteijn, J.A.; Lans, H.; Vermeulen, W.; Hoeijmakers, J.H. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol.,  2014, 15(7), 465-481.
[http://dx.doi.org/10.1038/nrm3822] [PMID: 24954209] 
[138] 
Welsh, C.; Day, R.; McGurk, C.; Masters, J.R.; Wood, R.D.; Köberle, B. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int. J. Cancer,  2004, 110(3), 352-361.
[http://dx.doi.org/10.1002/ijc.20134] [PMID: 15095299] 
[139] 
Köberle, B.; Masters, J.R.; Hartley, J.A.; Wood, R.D. Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Curr. Biol.,  1999, 9(5), 273-276.
[http://dx.doi.org/10.1016/S0960-9822(99)80118-3] [PMID: 10074455] 
[140] 
Neher, T.M.; Bodenmiller, D.; Fitch, R.W.; Jalal, S.I.; Turchi, J.J. Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin. Mol. Cancer Ther.,  2011, 10(10), 1796-1806.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0303] [PMID: 21846830] 
[141] 
Bochkarev, A.; Bochkareva, E.; Frappier, L.; Edwards, A.M. The crystal structure of the complex of replication protein A subunits RPA32 and RPA14 reveals a mechanism for single-stranded DNA binding. EMBO J.,  1999, 18(16), 4498-4504.
[http://dx.doi.org/10.1093/emboj/18.16.4498] [PMID: 10449415] 
[142] 
Jekimovs, C.; Bolderson, E.; Suraweera, A.; Adams, M.; O’Byrne, K.J.; Richard, D.J. Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising. Front. Oncol.,  2014, 4, 86.
[http://dx.doi.org/10.3389/fonc.2014.00086] [PMID: 24795863] 
[143] 
Glanzer, J.G.; Liu, S.; Wang, L.; Mosel, A.; Peng, A.; Oakley, G.G. RPA inhibition increases replication stress and suppresses tumor growth. Cancer Res.,  2014, 74(18), 5165-5172.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0306] [PMID: 25070753] 
[144] 
Mishra, A.K.; Dormi, S.S.; Turchi, A.M.; Woods, D.S.; Turchi, J.J. Chemical inhibitor targeting the replication protein A-DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer. Biochem. Pharmacol.,  2015, 93(1), 25-33.
[http://dx.doi.org/10.1016/j.bcp.2014.10.013] [PMID: 25449597] 
[145] 
Kumar, R.; Cheok, C.F. RIF1: a novel regulatory factor for DNA replication and DNA damage response signaling. DNA Repair (Amst.),  2014, 15, 54-59.
[http://dx.doi.org/10.1016/j.dnarep.2013.12.004] [PMID: 24462468] 
[146] 
Wang, H.; Zhao, A.; Chen, L.; Zhong, X.; Liao, J.; Gao, M.; Cai, M.; Lee, D.H.; Li, J.; Chowdhury, D.; Yang, Y.G.; Pfeifer, G.P.; Yen, Y.; Xu, X. Human RIF1 encodes an anti-apoptotic factor required for DNA repair. Carcinogenesis,  2009, 30(8), 1314-1319.
[http://dx.doi.org/10.1093/carcin/bgp136] [PMID: 19483192] 
[147] 
Jamil, S.; Mojtabavi, S.; Hojabrpour, P.; Cheah, S.; Duronio, V. An essential role for MCL-1 in ATR-mediated CHK1 phosphorylation. Mol. Biol. Cell,  2008, 19(8), 3212-3220.
[http://dx.doi.org/10.1091/mbc.e07-11-1171] [PMID: 18495871] 
[148] 
Zhang, F.; Shen, M.; Yang, L.; Yang, X.; Tsai, Y.; Keng, P.C.; Chen, Y.; Lee, S.O.; Chen, Y. Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer. Cancer Biol. Ther.,  2017, 18(8), 606-615.
[http://dx.doi.org/10.1080/15384047.2017.1345391] [PMID: 28686074] 
[149] 
Yu, Q.; Liu, Z.Y.; Chen, Q.; Lin, J.S. Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma. J. Huazhong Univ. Sci. Technolog. Med. Sci.,  2016, 36(4), 494-500.
[http://dx.doi.org/10.1007/s11596-016-1614-7] [PMID: 27465322] 
[150] 
Quinn, B.A.; Dash, R.; Azab, B.; Sarkar, S.; Das, S.K.; Kumar, S.; Oyesanya, R.A.; Dasgupta, S.; Dent, P.; Grant, S.; Rahmani, M.; Curiel, D.T.; Dmitriev, I.; Hedvat, M.; Wei, J.; Wu, B.; Stebbins, J.L.; Reed, J.C.; Pellecchia, M.; Sarkar, D.; Fisher, P.B. Targeting Mcl-1 for the therapy of cancer. Expert Opin. Investig. Drugs,  2011, 20(10), 1397-1411.
[http://dx.doi.org/10.1517/13543784.2011.609167] [PMID: 21851287] 
[151] 
Yamaguchi, R.; Lartigue, L.; Perkins, G. Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy. Pharmacol. Ther.,  2019, 195, 13-20.
[http://dx.doi.org/10.1016/j.pharmthera.2018.10.009] [PMID: 30347215] 
[152] 
Chen, G.; Magis, A.T.; Xu, K.; Park, D.; Yu, D.S.; Owonikoko, T.K.; Sica, G.L.; Satola, S.W.; Ramalingam, S.S.; Curran, W.J.; Doetsch, P.W.; Deng, X. Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy. J. Clin. Invest.,  2018, 128(1), 500-516.
[http://dx.doi.org/10.1172/JCI92742] [PMID: 29227281] 
[153] 
Guang, M.H.Z.; Kavanagh, E.L.; Dunne, L.P.; Dowling, P.; Zhang, L.; Lindsay, S.; Bazou, D.; Goh, C.Y.; Hanley, C.; Bianchi, G.; Anderson, K.C.; O’Gorman, P.; McCann, A. Targeting proteotoxic stress in cancer: a review of the role that protein quality control pathways play in oncogenesis. Cancers (Basel),  2019, 11(1)E66
[http://dx.doi.org/10.3390/cancers11010066] [PMID: 30634515] 
[154] 
Fu, Q.; Jiang, Y.; Zhang, D.; Liu, X.; Guo, J.; Zhao, J. Valosin-containing protein (VCP) promotes the growth, invasion, and metastasis of colorectal cancer through activation of STAT3 signaling. Mol. Cell. Biochem.,  2016, 418(1-2), 189-198.
[http://dx.doi.org/10.1007/s11010-016-2746-6] [PMID: 27344168] 
[155] 
Zhang, H.; Li, K.; Lin, Y.; Xing, F.; Xiao, X.; Cai, J.; Zhu, W.; Liang, J.; Tan, Y.; Fu, L.; Wang, F.; Yin, W.; Lu, B.; Qiu, P.; Su, X.; Gong, S.; Bai, X.; Hu, J.; Yan, G. Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma. Sci. Transl. Med.,  2017, 9(404)eaam7996
[http://dx.doi.org/10.1126/scitranslmed.aam7996] [PMID: 28835517] 
[156] 
Vance, R.E.; Cytosolic, D.N.A. Cytosolic DNA sensing: the field narrows. Immunity,  2016, 45(2), 227-228.
[http://dx.doi.org/10.1016/j.immuni.2016.08.006] [PMID: 27533006] 
[157] 
Chen, Q.; Sun, L.; Chen, Z.J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol.,  2016, 17(10), 1142-1149.
[http://dx.doi.org/10.1038/ni.3558] [PMID: 27648547] 
[158] 
Chen, Q.; Boire, A.; Jin, X.; Valiente, M.; Er, E.E.; Lopez-Soto, A.; Jacob, L.; Patwa, R.; Shah, H.; Xu, K.; Cross, J.R.; Massagué, J. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature,  2016, 533(7604), 493-498.
[http://dx.doi.org/10.1038/nature18268] [PMID: 27225120] 
[159] 
Lemos, H.; Mohamed, E.; Huang, L.; Ou, R.; Pacholczyk, G.; Arbab, A.S.; Munn, D.; Mellor, A.L. STING promotes the growth of tumors characterized by low Antigenicity via IDO activation. Cancer Res.,  2016, 76(8), 2076-2081.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1456] [PMID: 26964621] 
[160] 
Feng, X.; Liu, D.; Li, Z.; Bian, J. Bioactive modulators targeting STING adaptor in cGAS-STING pathway. Drug Discov. Today, 2019.
[http://dx.doi.org/10.1016/j.drudis.2019.11.007] [PMID: 31758915] 
[161] 
Sheridan, C. Drug developers switch gears to inhibit STING. Nat. Biotechnol.,  2019, 37(3), 199-201.
[http://dx.doi.org/10.1038/s41587-019-0060-z] [PMID: 30833772] 
[162] 
Haag, S.M.; Gulen, M.F.; Reymond, L.; Gibelin, A.; Abrami, L.; Decout, A.; Heymann, M.; van der Goot, F.G.; Turcatti, G.; Behrendt, R.; Ablasser, A. Targeting STING with covalent small-molecule inhibitors. Nature,  2018, 559(7713), 269-273.
[http://dx.doi.org/10.1038/s41586-018-0287-8] [PMID: 29973723] 
[163] 
Kumar, S.; Peng, X.; Daley, J.; Yang, L.; Shen, J.; Nguyen, N.; Bae, G.; Niu, H.; Peng, Y.; Hsieh, H.J.; Wang, L.; Rao, C.; Stephan, C.C.; Sung, P.; Ira, G.; Peng, G. Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells. Oncogenesis,  2017, 6(4)e319
[http://dx.doi.org/10.1038/oncsis.2017.15] [PMID: 28414320] 
[164] 
Plummer, R.; Middleton, M.; Wilson, R.; Jones, C.; Evans, J.; Robson, L.; Steinfeldt, H.; Kaufman, R.; Reich, S.; Calvert, A.H. First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors. J. Clin. Oncol.,  2005, 23(16), 208s-208s.
[http://dx.doi.org/10.1200/jco.2005.23.16_suppl.3065] 
[165] 
Papeo, G.; Posteri, H.; Borghi, D.; Busel, A.A.; Caprera, F.; Casale, E.; Ciomei, M.; Cirla, A.; Corti, E.; D’Anello, M.; Fasolini, M.; Forte, B.; Galvani, A.; Isacchi, A.; Khvat, A.; Krasavin, M.Y.; Lupi, R.; Orsini, P.; Perego, R.; Pesenti, E.; Pezzetta, D.; Rainoldi, S.; Riccardi-Sirtori, F.; Scolaro, A.; Sola, F.; Zuccotto, F.; Felder, E.R.; Donati, D.; Montagnoli, A. Discovery of 2-[1-(4,4-Difluorocyclohexyl) piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): a potent, orally available, and highly selective PARP-1 inhibitor for cancer therapy. J. Med. Chem.,  2015, 58(17), 6875-6898.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00680] [PMID: 26222319] 
[166] 
Sarkaria, J.N.; Tibbetts, R.S.; Busby, E.C.; Kennedy, A.P.; Hill, D.E.; Abraham, R.T. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res.,  1998, 58(19), 4375-4382.
[PMID: 9766667] 
[167] 
Blasina, A.; Price, B.D.; Turenne, G.A.; McGowan, C.H. Caffeine inhibits the checkpoint kinase ATM. Curr. Biol.,  1999, 9(19), 1135-1138.
[http://dx.doi.org/10.1016/S0960-9822(99)80486-2] [PMID: 10531013] 
[168] 
Maira, S.M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.; Brachmann, S.; Chène, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; García-Echeverría, C. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther.,  2008, 7(7), 1851-1863.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0017] [PMID: 18606717] 
[169] 
Biddlestone-Thorpe, L.; Sajjad, M.; Rosenberg, E.; Beckta, J.M.; Valerie, N.C.; Tokarz, M.; Adams, B.R.; Wagner, A.F.; Khalil, A.; Gilfor, D.; Golding, S.E.; Deb, S.; Temesi, D.G.; Lau, A.; O’Connor, M.J.; Choe, K.S.; Parada, L.F.; Lim, S.K.; Mukhopadhyay, N.D.; Valerie, K. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin. Cancer Res.,  2013, 19(12), 3189-3200.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-3408] [PMID: 23620409] 
[170] 
Stupp, R.; Hegi, M.E.; Gilbert, M.R.; Chakravarti, A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J. Clin. Oncol.,  2007, 25(26), 4127-4136.
[http://dx.doi.org/10.1200/JCO.2007.11.8554] [PMID: 17827463] 
[171] 
Rainey, M.D.; Charlton, M.E.; Stanton, R.V.; Kastan, M.B. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res.,  2008, 68(18), 7466-7474.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0763] [PMID: 18794134] 
[172] 
Min, J.; Guo, K.; Suryadevara, P.K.; Zhu, F.; Holbrook, G.; Chen, Y.; Feau, C.; Young, B.M.; Lemoff, A.; Connelly, M.C.; Kastan, M.B.; Guy, R.K. Optimization of a novel series of ataxia-telangiectasia mutated kinase inhibitors as potential radiosensitizing agents. J. Med. Chem.,  2016, 59(2), 559-577.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01092] [PMID: 26632965] 
[173] 
Nishida, H.; Tatewaki, N.; Nakajima, Y.; Magara, T.; Ko, K.M.; Hamamori, Y.; Konishi, T. Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res.,  2009, 37(17), 5678-5689.
[http://dx.doi.org/10.1093/nar/gkp593] [PMID: 19625493] 
[174] 
Anderson, V.E.; Walton, M.I.; Eve, P.D.; Boxall, K.J.; Antoni, L.; Caldwell, J.J.; Aherne, W.; Pearl, L.H.; Oliver, A.W.; Collins, I.; Garrett, M.D. CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors. Cancer Res.,  2011, 71(2), 463-472.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1252] [PMID: 21239475] 
[175] 
Matthews, T.P.; Jones, A.M.; Collins, I. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin. Drug Discov.,  2013, 8(6), 621-640.
[http://dx.doi.org/10.1517/17460441.2013.788496] [PMID: 23594139] 
[176] 
Itamochi, H.; Nishimura, M.; Oumi, N.; Kato, M.; Oishi, T.; Shimada, M.; Sato, S.; Naniwa, J.; Sato, S.; Kudoh, A.; Kigawa, J.; Harada, T. Checkpoint kinase inhibitor AZD7762 overcomes cisplatin resistance in clear cell carcinoma of the ovary. Int. J. Gynecol. Cancer,  2014, 24(1), 61-69.
[http://dx.doi.org/10.1097/IGC.0000000000000014] [PMID: 24362713] 
[177] 
Daud, A.I.; Ashworth, M.T.; Strosberg, J.; Goldman, J.W.; Mendelson, D.; Springett, G.; Venook, A.P.; Loechner, S.; Rosen, L.S.; Shanahan, F.; Parry, D.; Shumway, S.; Grabowsky, J.A.; Freshwater, T.; Sorge, C.; Kang, S.P.; Isaacs, R.; Munster, P.N. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J. Clin. Oncol.,  2015, 33(9), 1060-1066.
[http://dx.doi.org/10.1200/JCO.2014.57.5027] [PMID: 25605849] 
[178] 
Huang, F.; Motlekar, N.A.; Burgwin, C.M.; Napper, A.D.; Diamond, S.L.; Mazin, A.V. Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening. ACS Chem. Biol.,  2011, 6(6), 628-635.
[http://dx.doi.org/10.1021/cb100428c] [PMID: 21428443] 
[179] 
Zhu, J.; Chen, H.; Guo, X.E.; Qiu, X.L.; Hu, C.M.; Chamberlin, A.R.; Lee, W.H. Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors. Eur. J. Med. Chem.,  2015, 96, 196-208.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.021] [PMID: 25874343] 
[180] 
Hirai, H.; Iwasawa, Y.; Okada, M.; Arai, T.; Nishibata, T.; Kobayashi, M.; Kimura, T.; Kaneko, N.; Ohtani, J.; Yamanaka, K.; Itadani, H.; Takahashi-Suzuki, I.; Fukasawa, K.; Oki, H.; Nambu, T.; Jiang, J.; Sakai, T.; Arakawa, H.; Sakamoto, T.; Sagara, T.; Yoshizumi, T.; Mizuarai, S.; Kotani, H. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer Ther.,  2009, 8(11), 2992-3000.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0463] [PMID: 19887545] 
[181] 
Leijen, S.; van Geel, R.M.; Pavlick, A.C.; Tibes, R.; Rosen, L.; Razak, A.R.; Lam, R.; Demuth, T.; Rose, S.; Lee, M.A.; Freshwater, T.; Shumway, S.; Liang, L.W.; Oza, A.M.; Schellens, J.H.; Shapiro, G.I.; Phase, I. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J. Clin. Oncol.,  2016, 34(36), 4371-4380.
[http://dx.doi.org/10.1200/JCO.2016.67.5991] [PMID: 27601554] 
[182] 
Liu, W.; Zhou, M.; Li, Z.; Li, H.; Polaczek, P.; Dai, H.; Wu, Q.; Liu, C.; Karanja, K.K.; Popuri, V.; Shan, S.O.; Schlacher, K.; Zheng, L.; Campbell, J.L.; Shen, B. A selective small molecule DNA2 inhibitor for sensitization of human cancer cells to chemotherapy. EBio. Med.,  2016, 6, 73-86.
[http://dx.doi.org/10.1016/j.ebiom.2016.02.043] [PMID: 27211550] 
[183] 
Chung, J.G.; Chang, H.L.; Lin, W.C.; Wang, H.H.; Yeh, C.C.; Hung, C.F.; Li, Y.C. Inhibition of N-acetyltransferase activity and DNA-2-aminofluorene adducts by glycyrrhizic acid in human colon tumour cells. Food Chem. Toxicol.,  2000, 38(2-3), 163-172.
[http://dx.doi.org/10.1016/S0278-6915(99)00151-9] [PMID: 10717356] 
[184] 
Vlahos, C.J.; Matter, W.F.; Hui, K.Y.; Brown, R.F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem.,  1994, 269(7), 5241-5248.
[PMID: 8106507] 
[185] 
Tavecchio, M.; Munck, J.M.; Cano, C.; Newell, D.R.; Curtin, N.J. Further characterisation of the cellular activity of the DNA-PK inhibitor, NU7441, reveals potential cross-talk with homologous recombination. Cancer Chemother. Pharmacol.,  2012, 69(1), 155-164.
[http://dx.doi.org/10.1007/s00280-011-1662-4] [PMID: 21630086] 
[186] 
Tumey, L.N.; Bom, D.; Huck, B.; Gleason, E.; Wang, J.; Silver, D.; Brunden, K.; Boozer, S.; Rundlett, S.; Sherf, B.; Murphy, S.; Dent, T.; Leventhal, C.; Bailey, A.; Harrington, J.; Bennani, Y.L. The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors. Bioorg. Med. Chem. Lett.,  2005, 15(2), 277-281.
[http://dx.doi.org/10.1016/j.bmcl.2004.10.086] [PMID: 15603939] 
[187] 
Rai, G.; Vyjayanti, V.N.; Dorjsuren, D.; Simeonov, A.; Jadhav, A.; Wilson, D.M., III; Maloney, D.J. Synthesis, biological evaluation, and structure-activity relationships of a novel class of apurinic/apyrimidinic endonuclease 1 inhibitors. J. Med. Chem.,  2012, 55(7), 3101-3112.
[http://dx.doi.org/10.1021/jm201537d] [PMID: 22455312] 
[188] 
Jaiswal, A.S.; Banerjee, S.; Aneja, R.; Sarkar, F.H.; Ostrov, D.A.; Narayan, S. DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer. PLoS One,  2011, 6(2)e16691
[http://dx.doi.org/10.1371/journal.pone.0016691] [PMID: 21311763] 
[189] 
Lea, M.A. Recently identified and potential targets for colon cancer treatment. Future Oncol.,  2010, 6(6), 993-1002.
[http://dx.doi.org/10.2217/fon.10.53] [PMID: 20528236] 
[190] 
Glanzer, J.G.; Liu, S.; Oakley, G.G. Small molecule inhibitor of the RPA70 N-terminal protein interaction domain discovered using in silico and in vitro methods. Bioorg. Med. Chem.,  2011, 19(8), 2589-2595.
[http://dx.doi.org/10.1016/j.bmc.2011.03.012] [PMID: 21459001] 
[191] 
Sierecki, E.; Newton, A.C. Biochemical characterization of the phosphatase domain of the tumor suppressor PH domain leucine-rich repeat protein phosphatase. Biochemistry,  2014, 53(24), 3971-3981.
[http://dx.doi.org/10.1021/bi500428j] [PMID: 24892992] 
[192] 
Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science,  2013, 342(6165), 1432-1433.
[http://dx.doi.org/10.1126/science.342.6165.1432] [PMID: 24357284] 
[193] 
Rosenberg, S.A. Decade in review-cancer immunotherapy: entering the mainstream of cancer treatment. Nat. Rev. Clin. Oncol.,  2014, 11(11), 630-632.
[http://dx.doi.org/10.1038/nrclinonc.2014.174] [PMID: 25311350] 
[194] 
Mouw, K.W.; Goldberg, M.S.; Konstantinopoulos, P.A.; D’Andrea, A.D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov.,  2017, 7(7), 675-693.
[http://dx.doi.org/10.1158/2159-8290.CD-17-0226] [PMID: 28630051] 
[195] 
Harding, S.M.; Benci, J.L.; Irianto, J.; Discher, D.E.; Minn, A.J.; Greenberg, R.A. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature,  2017, 548(7668), 466-470.
[http://dx.doi.org/10.1038/nature23470] [PMID: 28759889] 
[196] 
Blatter, S.; Guyader, C.; Kucukosmanoglu, A.; Freriks, S.; de Visser, K.; Borst, P.; Rottenberg, S. Combining PD1-and CTLA4-inhibiting antibodies with cisplatin or PARP inhibition in an attempt to eradicate BRCA1-deficient mouse mammary tumors. Cancer Res.,  2015, 736.
[http://dx.doi.org/10.1158/1538-7445.AM2015-736] 
[197] 
Yap, T.A.; Krebs, M.G.; Postel-Vinay, S.; Bang, Y.J.; El-Khoueiry, A.; Abida, W.; Harrington, K.; Sundar, R.; Carter, L.; Castanon-Alvarez, E. Im, S.A.; Berges, A.; Khan, M.; Stephens, C.; Ross, G.; Soria, J.C., Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. Eur. J. Cancer,  2016, 69, S2-S2.
[http://dx.doi.org/10.1016/S0959-8049(16)32607-7] 
[198] 
Lowe, S.W.; Lin, A.W. Apoptosis in cancer. Carcinogenesis,  2000, 21(3), 485-495.
[http://dx.doi.org/10.1093/carcin/21.3.485] [PMID: 10688869] 
[199] 
Collado, M.; Blasco, M.A.; Serrano, M. Cellular senescence in cancer and aging. Cell,  2007, 130(2), 223-233.
[http://dx.doi.org/10.1016/j.cell.2007.07.003] [PMID: 17662938] 
[200] 
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol.,  2013, 75, 685-705.
[http://dx.doi.org/10.1146/annurev-physiol-030212-183653] [PMID: 23140366] 
[201] 
Collado, M.; Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer,  2010, 10(1), 51-57.
[http://dx.doi.org/10.1038/nrc2772] [PMID: 20029423] 
[202] 
Larsson, L.G. Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. Semin. Cancer Biol.,  2011, 21(6), 367-376.
[http://dx.doi.org/10.1016/j.semcancer.2011.10.005] [PMID: 22037160] 
[203] 
Sliwinska, M.A.; Mosieniak, G.; Wolanin, K.; Babik, A.; Piwocka, K.; Magalska, A.; Szczepanowska, J.; Fronk, J.; Sikora, E. Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells. Mech. Ageing Dev.,  2009, 130(1-2), 24-32.
[http://dx.doi.org/10.1016/j.mad.2008.04.011] [PMID: 18538372] 
[204] 
Kasper, M.; Barth, K. Bleomycin and its role in inducing apoptosis and senescence in lung cells - modulating effects of caveolin-1. Curr. Cancer Drug Targets,  2009, 9(3), 341-353.
[http://dx.doi.org/10.2174/156800909788166501] [PMID: 19442053] 
[205] 
González-Billalabeitia, E.; Seitzer, N.; Song, S.J.; Song, M.S.; Patnaik, A.; Liu, X.S.; Epping, M.T.; Papa, A.; Hobbs, R.M.; Chen, M.; Lunardi, A.; Ng, C.; Webster, K.A.; Signoretti, S.; Loda, M.; Asara, J.M.; Nardella, C.; Clohessy, J.G.; Cantley, L.C.; Pandolfi, P.P. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer Discov.,  2014, 4(8), 896-904.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0230] [PMID: 24866151] 
[206] 
Castedo, M.; Perfettini, J.L.; Roumier, T.; Andreau, K.; Medema, R.; Kroemer, G. Cell death by mitotic catastrophe: a molecular definition. Oncogene,  2004, 23(16), 2825-2837.
[http://dx.doi.org/10.1038/sj.onc.1207528] [PMID: 15077146] 
[207] 
Denisenko, T.V.; Sorokina, I.V.; Gogvadze, V.; Zhivotovsky, B. Mitotic catastrophe and cancer drug resistance: A link that must to be broken. Drug Resist. Updat.,  2016, 24, 1-12.
[http://dx.doi.org/10.1016/j.drup.2015.11.002] [PMID: 26830311] 
[208] 
Arun, B.; Akar, U.; Gutierrez-Barrera, A.M.; Hortobagyi, G.N.; Ozpolat, B. The PARP inhibitor AZD2281 (Olaparib) induces autophagy/mitophagy in BRCA1 and BRCA2 mutant breast cancer cells. Int. J. Oncol.,  2015, 47(1), 262-268.
[http://dx.doi.org/10.3892/ijo.2015.3003] [PMID: 25975349] 
[209] 
Galluzzi, L.; Kroemer, G. Necroptosis: a specialized pathway of programmed necrosis. Cell,  2008, 135(7), 1161-1163.
[http://dx.doi.org/10.1016/j.cell.2008.12.004] [PMID: 19109884] 
[210] 
Han, W.; Li, L.; Qiu, S.; Lu, Q.; Pan, Q.; Gu, Y.; Luo, J.; Hu, X. Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol. Cancer Ther.,  2007, 6(5), 1641-1649.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0511] [PMID: 17513612] 
[211] 
Brumatti, G.; Ma, C.; Lalaoui, N.; Nguyen, N.Y.; Navarro, M.; Tanzer, M.C.; Richmond, J.; Ghisi, M.; Salmon, J.M.; Silke, N.; Pomilio, G.; Glaser, S.P.; de Valle, E.; Gugasyan, R.; Gurthridge, M.A.; Condon, S.M.; Johnstone, R.W.; Lock, R.; Salvesen, G.; Wei, A.; Vaux, D.L.; Ekert, P.G.; Silke, J. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci. Transl. Med.,  2016, 8(339)339ra69
[http://dx.doi.org/10.1126/scitranslmed.aad3099] [PMID: 27194727] 
[212] 
Jaspers, J.E.; Sol, W.; Kersbergen, A.; Schlicker, A.; Guyader, C.; Xu, G.; Wessels, L.; Borst, P.; Jonkers, J.; Rottenberg, S. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance. Cancer Res.,  2015, 75(4), 732-741.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0839] [PMID: 25511378] 
[213] 
Ruiz, S.; Mayor-Ruiz, C.; Lafarga, V.; Murga, M.; Vega-Sendino, M.; Ortega, S.; Fernandez-Capetillo, O. A Genome-wide CRISPR screen identifies CDC25A as a determinant of sensitivity to ATR inhibitors. Mol. Cell,  2016, 62(2), 307-313.
[http://dx.doi.org/10.1016/j.molcel.2016.03.006] [PMID: 27067599] 
[214] 
Brown, J.S.; O’Carrigan, B.; Jackson, S.P.; Yap, T.A. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov.,  2017, 7(1), 20-37.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0860] [PMID: 28003236] 
[215] 
Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug resistance in cancer: an overview. Cancers (Basel),  2014, 6(3), 1769-1792.
[http://dx.doi.org/10.3390/cancers6031769] [PMID: 25198391] 
[216] 
Graziani, G.; Szabó, C. Clinical perspectives of PARP inhibitors. Pharmacol. Res.,  2005, 52(1), 109-118.
[http://dx.doi.org/10.1016/j.phrs.2005.02.013] [PMID: 15911339] 
[217] 
Livraghi, L.; Garber, J.E. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med.,  2015, 13, 188.
[http://dx.doi.org/10.1186/s12916-015-0425-1] [PMID: 26268938] 
[218] 
Helleday, T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol. Oncol.,  2011, 5(4), 387-393.
[http://dx.doi.org/10.1016/j.molonc.2011.07.001] [PMID: 21821475] 
[219] 
Chan, D.A.; Giaccia, A.J. Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics. Cell Cycle,  2008, 7(19), 2987-2990.
[http://dx.doi.org/10.4161/cc.7.19.6776] [PMID: 18818511] 
[220] 
Nijman, S.M. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett.,  2011, 585(1), 1-6.
[http://dx.doi.org/10.1016/j.febslet.2010.11.024] [PMID: 21094158] 
[221] 
Feng, Z.; Scott, S.P.; Bussen, W.; Sharma, G.G.; Guo, G.; Pandita, T.K.; Powell, S.N. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl. Acad. Sci. USA,  2011, 108(2), 686-691.
[http://dx.doi.org/10.1073/pnas.1010959107] [PMID: 21148102] 
[222] 
McManus, K.J.; Barrett, I.J.; Nouhi, Y.; Hieter, P. Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing. Proc. Natl. Acad. Sci. USA,  2009, 106(9), 3276-3281.
[http://dx.doi.org/10.1073/pnas.0813414106] [PMID: 19218431] 
[223] 
Mengwasser, K.E.; Adeyemi, R.O.; Leng, Y.; Choi, M.Y.; Clairmont, C.; D’Andrea, A.D.; Elledge, S.J. Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Mol. Cell,  2019, 73(5), 885-899.e6.
[http://dx.doi.org/10.1016/j.molcel.2018.12.008] [PMID: 30686591] 
[224] 
Skrott, Z.; Mistrik, M.; Andersen, K.K.; Friis, S.; Majera, D.; Gursky, J.; Ozdian, T.; Bartkova, J.; Turi, Z.; Moudry, P.; Kraus, M.; Michalova, M.; Vaclavkova, J.; Dzubak, P.; Vrobel, I.; Pouckova, P.; Sedlacek, J.; Miklovicova, A.; Kutt, A.; Li, J.; Mattova, J.; Driessen, C.; Dou, Q.P.; Olsen, J.; Hajduch, M.; Cvek, B.; Deshaies, R.J.; Bartek, J. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature,  2017, 552(7684), 194-199.
[http://dx.doi.org/10.1038/nature25016] [PMID: 29211715] 
[225] 
Sleire, L.; Førde, H.E.; Netland, I.A.; Leiss, L.; Skeie, B.S.; Enger, P.O. Drug repurposing in cancer. Pharmacol. Res.,  2017, 124, 74-91.
[http://dx.doi.org/10.1016/j.phrs.2017.07.013] [PMID: 28712971] 
[226] 
LaMontagne, K.R.; Butler, J.; Borowski, V.B.; Fuentes-Pesquera, A.R.; Blevitt, J.M.; Huang, S.; Li, R.; Connolly, P.J.; Greenberger, L.M. A highly selective, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor has potent activity in vitro and in vivo. Angiogenesis,  2009, 12(3), 287-296.
[http://dx.doi.org/10.1007/s10456-009-9151-7] [PMID: 19544081] 
[227] 
Kaplan, A.R.; Gueble, S.E.; Liu, Y.; Oeck, S.; Kim, H.; Yun, Z.; Glazer, P.M. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Sci. Transl. Med.,  2019, 11(492)eaav4508
[http://dx.doi.org/10.1126/scitranslmed.aav4508] [PMID: 31092693] 
[228] 
Lu, X.H.; Mattis, V.B.; Wang, N.; Al-Ramahi, I.; van den Berg, N.; Fratantoni, S.A.; Waldvogel, H.; Greiner, E.; Osmand, A.; Elzein, K.; Xiao, J.; Dijkstra, S.; de Pril, R.; Vinters, H.V.; Faull, R.; Signer, E.; Kwak, S.; Marugan, J.J.; Botas, J.; Fischer, D.F.; Svendsen, C.N.; Munoz-Sanjuan, I.; Yang, X.W. Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington’s disease. Sci. Transl. Med.,  2014, 6(268)268ra178
[http://dx.doi.org/10.1126/scitranslmed.3010523] [PMID: 25540325] 
Rights & Permissions Print Cite
Article Metrics
26
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867327666200224102309	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

靶向肿瘤治疗中DN A损伤反应关键蛋白的小分子抑制剂

摘要

当代药物化学

靶向肿瘤治疗中DN A损伤反应关键蛋白的小分子抑制剂

摘要 Play Pause

Related Journals

Related Books

Related Articles

摘要
