Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Decoding the Mechanism of Drugs of Heterocyclic Nature against Hepatocellular Carcinoma

Author(s): Ayana R Kumar, Anitha L, Bhagyalakshmi Nair, Bijo Mathew, Sinoy Sugunan* and Lekshmi R. Nath*

Volume 23, Issue 8, 2023

Published on: 15 June, 2022

Page: [882 - 893] Pages: 12

DOI: 10.2174/1871520622666220418115310

Price: $65

conference banner
Abstract

Objectives: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and accounts for ~90% of cases, with an approximated incidence of >1 million cases by 2025. Currently, the backbone of HCC therapy is the oral multi-kinase inhibitor, Sorafenib, which consists of a Pyridine heterocycle ring system. This review highlights the introspective characteristics of seven anticancer drugs of heterocyclic nature against HCC along with their structural activity relationships and molecular targets.

Methods: Literature collection was performed using PubMed, Google Scholar, SCOPUS, and Cross ref. Additional information was taken from the official website of the FDA and GLOBOCAN.

Key findings/ Results: Based on the available literature, approved heterocyclic compounds show promising results against HCC, including Sorafenib (Pyridine), Regorafenib (Pyridine), Lenvatinib (Quinoline), Cabozantinib (Quinoline), Gemcitabine (Pyrimidine), 5-Fluorouracil (Pyrimidine)and Capecitabine (Pyrimidine), their mechanism of action and key aspects regarding its structural activity were included in the review.

Conclusion: Heterocyclic compounds represent almost two-thirds of the novel drugs approved by FDA between 2010 and 2020 against Cancer. This review summarizes the clinical relevance, mechanism of action, structural activity relationship, and challenges of the seven available anticancer drugs with heterocyclic ring systems against HCC.

Keywords: Heterocyclic compounds, hepatocellular carcinoma, structural activity relationship, gemcitabine, 5-Fluorouracil, sorafenib, cancer.

« Previous Next »
Graphical Abstract

[1]
Kole, C.; Charalampakis, N.; Tsakatikas, S.; Vailas, M.; Moris, D.; Gkotsis, E.; Kykalos, S.; Karamouzis, M.V.; Schizas, D. Immunotherapy for hepatocellular carcinoma: A 2021 update. Cancers (Basel), 2020, 12(10), 2859.
[http://dx.doi.org/10.3390/cancers12102859] [PMID: 33020428]
[2]
International Agency for Research on Cancer. GLOBOCAN 2018. IARC 2020. Available from: https://gco.iarc.fr/today/online-analysis-map
[3]
Razavi, H. Global epidemiology of viral hepatitis. Gastroenterol. Clin., 2020, 49(2), 179-189.
[http://dx.doi.org/10.1016/j.gtc.2020.01.001] [PMID: 32389357]
[4]
Rawla, P.; Sunkara, T.; Muralidharan, P.; Raj, J.P. Update in global trends and aetiology of hepatocellular carcinoma. Contemp. Oncol. (Pozn.), 2018, 22(3), 141-150.
[http://dx.doi.org/10.5114/wo.2018.78941] [PMID: 30455585]
[5]
Schulze, K.; Imbeaud, S.; Letouzé, E.; Alexandrov, L.B.; Calderaro, J.; Rebouissou, S.; Couchy, G.; Meiller, C.; Shinde, J.; Soysouvanh, F.; Calatayud, A.L.; Pinyol, R.; Pelletier, L.; Balabaud, C.; Laurent, A.; Blanc, J.F.; Mazzaferro, V.; Calvo, F.; Villanueva, A.; Nault, J.C.; Bioulac-Sage, P.; Stratton, M.R.; Llovet, J.M.; Zucman-Rossi, J. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet., 2015, 47(5), 505-511.
[http://dx.doi.org/10.1038/ng.3252] [PMID: 25822088]
[6]
Garuti, F.; Neri, A.; Avanzato, F.; Gramenzi, A.; Rampoldi, D.; Rucci, P.; Farinati, F.; Giannini, E.G.; Piscaglia, F.; Rapaccini, G.L.; Di Marco, M.; Caturelli, E.; Zoli, M.; Sacco, R.; Cabibbo, G.; Marra, F.; Mega, A.; Morisco, F.; Gasbarrini, A.; Svegliati-Baroni, G.; Foschi, F.G.; Missale, G.; Masotto, A.; Nardone, G.; Raimondo, G.; Azzaroli, F.; Vidili, G.; Brunetto, M.R.; Trevisani, F. The changing scenario of hepatocellular carcinoma in Italy: an update. Liver Int., 2021, 41(3), 585-597.
[http://dx.doi.org/10.1111/liv.14735] [PMID: 33219585]
[7]
Zucman-Rossi, J.; Villanueva, A.; Nault, J.C.; Llovet, J.M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 2015, 149(5), 1226-1239.e4.
[http://dx.doi.org/10.1053/j.gastro.2015.05.061] [PMID: 26099527]
[8]
Jain, R.K.; Tong, R.T.; Munn, L.L. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res., 2007, 67(6), 2729-2735.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4102] [PMID: 17363594]
[9]
Kumar, A.R.; Devan, A.R.; Nair, B.; Nath, L.R. Anti-VEGF mediated immunomodulatory role of phytochemicals: scientific exposition for plausible HCC treatment. Curr. Drug Targets, 2021, 22(11), 1288-1316.
[http://dx.doi.org/10.2174/1389450122666210203194036] [PMID: 33538672]
[10]
Lopes-Coelho, F.; Martins, F.; Pereira, S.A.; Serpa, J. Anti-angiogenic therapy: Current challenges and future perspectives. Int. J. Mol. Sci., 2021, 22(7), 3765.
[http://dx.doi.org/10.3390/ijms22073765] [PMID: 33916438]
[11]
Dvorak, H.F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol., 2002, 20(21), 4368-4380.
[http://dx.doi.org/10.1200/JCO.2002.10.088] [PMID: 12409337]
[12]
Fukumura, D.; Kashiwagi, S.; Jain, R.K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer, 2006, 6(7), 521-534.
[http://dx.doi.org/10.1038/nrc1910] [PMID: 16794635]
[13]
Gunasekaran, G.; Bekki, Y.; Lourdusamy, V.; Schwartz, M. Surgical treatments of hepatobiliary cancers. Hepatology, 2021, 73(S1)(Suppl. 1), 128-136.
[http://dx.doi.org/10.1002/hep.31325] [PMID: 32438491]
[14]
Manas, D.; Bell, J.K.; Mealing, S.; Davies, H.; Baker, H.; Holmes, H.; Hubner, R.A. The cost-effectiveness of Thera Sphere in patients with hepatocellular carcinoma who are eligible for transarterial embolization. Eur. J. Surg. Oncol., 2021, 47(2), 401-408.
[http://dx.doi.org/10.1016/j.ejso.2020.08.027] [PMID: 32958370]
[15]
Colagrande, S.; Inghilesi, A.L.; Aburas, S.; Taliani, G.G.; Nardi, C.; Marra, F. Challenges of advanced hepatocellular carcinoma. World J. Gastroenterol., 2016, 22(34), 7645-7659.
[http://dx.doi.org/10.3748/wjg.v22.i34.7645] [PMID: 27678348]
[16]
Devan, A.R.; Kumar, A.R.; Nair, B.; Anto, N.P.; Muraleedharan, A.; Mathew, B.; Kim, H.; Nath, L.R. Insights into an immunotherapeutic approach to combat multidrug resistance in hepatocellular carcinoma. Pharmaceuticals (Basel), 2021, 14(7), 656.
[http://dx.doi.org/10.3390/ph14070656] [PMID: 34358082]
[17]
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M.A. Al-Othman, Z.; Al-Warthan, A.; Marsin, M. Heterocyclic scaffolds: centrality in anticancer drug development. Curr. Drug Targets, 2015, 16(7), 711-734.
[http://dx.doi.org/10.2174/1389450116666150309115922] [PMID: 25751009]
[18]
Heravi, M.M.; Zadsirjan, V. Prescribed drugs containing nitrogen heterocycles: an overview. RSC Advances, 2020, 10(72), 44247-44311.
[http://dx.doi.org/10.1039/D0RA09198G]
[19]
Komeilizadeh, H. Does nature prefer heterocycles? Iran. J. Pharm. Res., 2010, (4), 229-230.
[20]
Evstigneev, M.P. Physicochemical mechanisms of synergistic biological action of combinations of aromatic heterocyclic compounds. Org. Chem. Int., 2013, 2013, 2013.
[http://dx.doi.org/10.1155/2013/278143]
[21]
Avula, S.K.; Das, B.; Csuk, R.; Al-Harrasi, A. Naturally occurring o-heterocycles as anticancer agents. Anticancer. Agents Med. Chem., 2021, 21.
[http://dx.doi.org/10.2174/1871520621666211108091444] [PMID: 34749628]
[22]
Aydoğan, F.; Turgut, Z.; Yolaçan, Ç.; Öcal, N. The biological activities of new heterocylic compounds containing nitrogen and sulphur. Biodiversity, 2002, 371-374.
[http://dx.doi.org/10.1007/978-1-4419-9242-0_49]
[23]
Top Prescription Drugs by U.S. Sales 2019 Statistic. 2019. Available from: http://www.statista.com/statistics/258010/top-branded-drugs-based-on-retail-sales-in-the-us/
[24]
Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol., 2010, 14(3), 347-361.
[http://dx.doi.org/10.1016/j.cbpa.2010.02.018] [PMID: 20303320]
[25]
Gomtsyan, A. Heterocycles in drugs and drug discovery. Chem. Heterocycl. Compd., 2012, 48(1), 7-10.
[http://dx.doi.org/10.1007/s10593-012-0960-z]
[26]
Barresi, V.; Bonaccorso, C.; Cristaldi, D.A.; Modica, M.N.; Musso, N.; Pittalà, V.; Salerno, L.; Fortuna, C.G. Synthesis and experimental validation of new designed heterocyclic compounds with antiproliferative activity versus breast cancer cell lines mcf-7 and mda-mb-231. J. Chem., 2017, 2017, 1-10.
[http://dx.doi.org/10.1155/2017/9729284]
[27]
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[28]
Kidwai, M.; Venkataramanan, R.; Mohan, R.; Sapra, P. Cancer chemotherapy and heterocyclic compounds. Curr. Med. Chem., 2002, 9(12), 1209-1228.
[http://dx.doi.org/10.2174/0929867023370059] [PMID: 12052173]
[29]
Broughton, H.B.; Watson, I.A. Selection of heterocycles for drug design. J. Mol. Graph. Model., 2004, 23(1), 51-58.
[http://dx.doi.org/10.1016/j.jmgm.2004.03.016] [PMID: 15331053]
[30]
Alvárez-Builla, J.; Barluenga, J. Heterocyclic compounds: An introduction. Mod. Heterocycl. Chem., 2011, 1, 1-9.
[31]
Lang, D.K.; Kaur, R.; Arora, R.; Saini, B.; Arora, S. Nitrogen-containing heterocycles as anticancer agents: An overview. Anticancer. Agents Med. Chem., 2020, 20(18), 2150-2168.
[32]
Hou, J.; Zhao, W.; Huang, Z.N.; Yang, S.M.; Wang, L.J.; Jiang, Y.; Zhou, Z.S.; Zheng, M.Y.; Jiang, J.L.; Li, S.H.; Li, F.N. Evaluation of novel N-(piperidine-4-yl)benzamide derivatives as potential cell cycle inhibitors in HepG2 Cells. Chem. Biol. Drug Des., 2015, 86(2), 223-231.
[http://dx.doi.org/10.1111/cbdd.12484] [PMID: 25430863]
[33]
Zhu, A.X.; Duda, D.G.; Sahani, D.V.; Jain, R.K. HCC and angiogenesis: possible targets and future directions. Nat. Rev. Clin. Oncol., 2011, 8(5), 292-301.
[http://dx.doi.org/10.1038/nrclinonc.2011.30] [PMID: 21386818]
[34]
Zheng, L.; Yang, W.; Wu, F.; Wang, C.; Yu, L.; Tang, L.; Qiu, B.; Li, Y.; Guo, L.; Wu, M.; Feng, G.; Zou, D.; Wang, H. Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin. Cancer Res., 2013, 19(19), 5372-5380.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0203] [PMID: 23942093]
[35]
Khoo, T. S. W. L.; Rehman, A.; Olynyk, J. K. Tyrosine kinase inhibitors in the treatment of hepatocellular carcinoma. J.E.E, 2019, 127-139.
[36]
Spinzi, G.; Paggi, S. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(23), 2497-2498.
[http://dx.doi.org/10.1056/NEJMc081780] [PMID: 19052134]
[37]
Cheng, A.L.; Kang, Y.K.; Chen, Z.; Tsao, C.J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T.S.; Xu, J.; Sun, Y.; Liang, H.; Liu, J.; Wang, J.; Tak, W.Y.; Pan, H.; Burock, K.; Zou, J.; Voliotis, D.; Guan, Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol., 2009, 10(1), 25-34.
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[38]
Tovoli, F; Granito, A; De Lorenzo, S; Bolondi, L Regorafenib for the treatment of hepatocellular carcinoma. Drugs of Today (Barcelona, Spain: 1998), 2018, 54(1), 5-13.
[http://dx.doi.org/10.1358/dot.2018.54.1.2736667]
[39]
Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; Gerolami, R.; Masi, G.; Ross, P.J.; Song, T.; Bronowicki, J.P.; Ollivier-Hourmand, I.; Kudo, M.; Cheng, A.L.; Llovet, J.M.; Finn, R.S.; LeBerre, M.A.; Baumhauer, A.; Meinhardt, G.; Han, G. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064), 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[40]
Schlumberger, M.; Tahara, M.; Wirth, L.J.; Robinson, B.; Brose, M.S.; Elisei, R.; Habra, M.A.; Newbold, K.; Shah, M.H.; Hoff, A.O.; Gianoukakis, A.G.; Kiyota, N.; Taylor, M.H.; Kim, S.B.; Krzyzanowska, M.K.; Dutcus, C.E.; de las Heras, B.; Zhu, J.; Sherman, S.I. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med., 2015, 372(7), 621-630.
[http://dx.doi.org/10.1056/NEJMoa1406470] [PMID: 25671254]
[41]
Motzer, R.J.; Hutson, T.E.; Glen, H.; Michaelson, M.D.; Molina, A.; Eisen, T.; Jassem, J.; Zolnierek, J.; Maroto, J.P.; Mellado, B.; Melichar, B.; Tomasek, J.; Kremer, A.; Kim, H.J.; Wood, K.; Dutcus, C.; Larkin, J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol., 2015, 16(15), 1473-1482.
[http://dx.doi.org/10.1016/S1470-2045(15)00290-9] [PMID: 26482279]
[42]
Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A.D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.C.; Joly, A.H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther., 2011, 10(12), 2298-2308.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0264] [PMID: 21926191]
[43]
Abou-Alfa, G.K.; Meyer, T.; Cheng, A.L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B.Y.; Cicin, I.; Merle, P.; Chen, Y.; Park, J.W.; Blanc, J.F.; Bolondi, L.; Klümpen, H.J.; Chan, S.L.; Zagonel, V.; Pressiani, T.; Ryu, M.H.; Venook, A.P.; Hessel, C.; Borgman-Hagey, A.E.; Schwab, G.; Kelley, R.K. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med., 2018, 379(1), 54-63.
[http://dx.doi.org/10.1056/NEJMoa1717002] [PMID: 29972759]
[44]
Qin, S.; Bai, Y.; Lim, H.Y.; Thongprasert, S.; Chao, Y.; Fan, J.; Yang, T.S.; Bhudhisawasdi, V.; Kang, W.K.; Zhou, Y.; Lee, J.H.; Sun, Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J. Clin. Oncol., 2013, 31(28), 3501-3508.
[http://dx.doi.org/10.1200/JCO.2012.44.5643] [PMID: 23980077]
[45]
Hu, Z.; Lv, G.; Li, Y.; Li, E.; Li, H.; Zhou, Q.; Yang, B.; Cao, W. Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound. J. Exp. Clin. Cancer Res., 2016, 35(1), 71.
[http://dx.doi.org/10.1186/s13046-016-0349-4] [PMID: 27102814]
[46]
Hammond, J.S.; Franko, J.; Holloway, S.E.; Heckman, J.T.; Orons, P.D.; Gamblin, T.C. Gemcitabine transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma. Hepatogastroenterology, 2014, 61(133), 1339-1343.
[PMID: 25436307]
[47]
Dyawanapelly, S.; Kumar, A.; Chourasia, M.K. Lessons learned from gemcitabine: impact of therapeutic carrier systems and gemcitabine’s drug conjugates on cancer therapy. Crit. Rev. Ther. Drug Carrier Syst., 2017, 34(1), 63-96.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2017017912] [PMID: 28322141]
[48]
Sloat, B.R.; Sandoval, M.A.; Li, D.; Chung, W.G.; Lansakara-P, D.S.; Proteau, P.J.; Kiguchi, K.; DiGiovanni, J.; Cui, Z. In vitro and in vivo anti-tumor activities of a gemcitabine derivative carried by nanoparticles. Int. J. Pharm., 2011, 409(1-2), 278-288.
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.037] [PMID: 21371545]
[49]
Federico, C.; Morittu, V.M.; Britti, D.; Trapasso, E.; Cosco, D. Gemcitabine-loaded liposomes: rationale, potentialities and future perspectives. Int. J. Nanomedicine, 2012, 7, 5423-5436.
[PMID: 23139626]
[50]
Yoon, S.; Huang, K.W.; Reebye, V.; Spalding, D.; Przytycka, T.M.; Wang, Y.; Swiderski, P.; Li, L.; Armstrong, B.; Reccia, I.; Zacharoulis, D.; Dimas, K.; Kusano, T.; Shively, J.; Habib, N.; Rossi, J.J. Aptamer-drug conjugates of active metabolites of nucleoside analogs and cytotoxic agents inhibit pancreatic tumor cell growth. Mol. Ther. Nucleic Acids, 2017, 6, 80-88.
[http://dx.doi.org/10.1016/j.omtn.2016.11.008] [PMID: 28325302]
[51]
Karampelas, T.; Skavatsou, E.; Argyros, O.; Fokas, D.; Tamvakopoulos, C. Gemcitabine based peptide conjugate with improved metabolic properties and dual mode of efficacy. Mol. Pharm., 2017, 14(3), 674-685.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00961] [PMID: 28099809]
[52]
Sho, T.; Nakanishi, M.; Morikawa, K.; Ohara, M.; Kawagishi, N.; Izumi, T.; Umemura, M.; Ito, J.; Nakai, M.; Suda, G.; Ogawa, K.; Chuma, M.; Meguro, T.; Nakamura, M.; Nagasaka, A.; Horimoto, H.; Yamamoto, Y.; Sakamoto, N. A phase I study of combination therapy with sorafenib and 5-fluorouracil in patients with advanced hepatocellular carcinoma. Drugs R D., 2017, 17(3), 381-388.
[http://dx.doi.org/10.1007/s40268-017-0187-7] [PMID: 28573606]
[53]
Dong, N.; Shi, X.; Wang, S.; Gao, Y.; Kuang, Z.; Xie, Q.; Li, Y.; Deng, H.; Wu, Y.; Li, M.; Li, J.L. M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br. J. Cancer, 2019, 121(1), 22-33.
[http://dx.doi.org/10.1038/s41416-019-0482-x] [PMID: 31130723]
[54]
Llovet, J.M.; Peña, C.E.; Lathia, C.D.; Shan, M.; Meinhardt, G.; Bruix, J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin. Cancer Res., 2012, 18(8), 2290-2300.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2175] [PMID: 22374331]
[55]
Hsu, M.H.; Hsu, S.M.; Kuo, Y.C.; Liu, C.Y.; Hsieh, C.Y.; Twu, Y.C.; Wang, C.K.; Wang, Y.H.; Liao, Y.J. Treatment with low-dose sorafenib in combination with a novel benzimidazole derivative bearing a pyrolidine side chain provides synergistic anti-proliferative effects against human liver cancer. RSC Advances, 2017, 7(26), 16253-16263.
[http://dx.doi.org/10.1039/C6RA28281D]
[56]
Shah, K.; Panchal, S.; Patel, B. Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol. Res., 2021, 167105532
[http://dx.doi.org/10.1016/j.phrs.2021.105532] [PMID: 33677106]
[57]
Chen, B.; Dodge, M.E.; Tang, W.; Lu, J.; Ma, Z.; Fan, C.W.; Wei, S.; Hao, W.; Kilgore, J.; Williams, N.S.; Roth, M.G.; Amatruda, J.F.; Chen, C.; Lum, L. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol., 2009, 5(2), 100-107.
[http://dx.doi.org/10.1038/nchembio.137] [PMID: 19125156]
[58]
Proffitt, K.D.; Madan, B.; Ke, Z.; Pendharkar, V.; Ding, L.; Lee, M.A.; Hannoush, R.N.; Virshup, D.M. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res., 2013, 73(2), 502-507.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2258] [PMID: 23188502]
[59]
You, L.; Zhang, C.; Yarravarapu, N.; Morlock, L.; Wang, X.; Zhang, L.; Williams, N.S.; Lum, L.; Chen, C. Development of a triazole class of highly potent Porcn inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(24), 5891-5895.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.012] [PMID: 27876319]
[60]
Ho, S.Y.; Alam, J.; Jeyaraj, D.A.; Wang, W.; Lin, G.R.; Ang, S.H.; Tan, E.S.W.; Lee, M.A.; Ke, Z.; Madan, B.; Virshup, D.M.; Ding, L.J.; Manoharan, V.; Chew, Y.S.; Low, C.B.; Pendharkar, V.; Sangthongpitag, K.; Hill, J.; Keller, T.H.; Poulsen, A. Scaffold hopping and optimization of maleimide based porcupine inhibitors. J. Med. Chem., 2017, 60(15), 6678-6692.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00662] [PMID: 28671458]
[61]
Han, Z.G. Functional genomic studies: insights into the pathogenesis of liver cancer. Annu. Rev. Genomics Hum. Genet., 2012, 13(1), 171-205.
[http://dx.doi.org/10.1146/annurev-genom-090711-163752] [PMID: 22703171]
[62]
Taniguchi, K.; Roberts, L.R.; Aderca, I.N.; Dong, X.; Qian, C.; Murphy, L.M.; Nagorney, D.M.; Burgart, L.J.; Roche, P.C.; Smith, D.I.; Ross, J.A.; Liu, W. Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene, 2002, 21(31), 4863-4871.
[http://dx.doi.org/10.1038/sj.onc.1205591] [PMID: 12101426]
[63]
Al-Issa, S.A. Synthesis and anticancer activity of some fused pyrimidines and related heterocycles. Saudi Pharm. J., 2013, 21(3), 305-316.
[http://dx.doi.org/10.1016/j.jsps.2012.09.002] [PMID: 23960847]
[64]
Pearce, S. The importance of heterocyclic compounds in anti-cancer drug design; Drug Discovery, 2017, p. 67.
[65]
Park, R.; Lopes da Silva, L.; Nissaisorakarn, V.; Riano, I.; Williamson, S.; Sun, W.; Saeed, A. Comparison of efficacy of systemic therapies in advanced hepatocellular carcinoma: updated systematic review and frequentist network meta-analysis of randomized controlled trials. J. Hepatocell. Carcinoma, 2021, 8, 145-154.
[http://dx.doi.org/10.2147/JHC.S268305] [PMID: 33791250]
[66]
Lang, L. FDA approves sorafenib for patients with inoperable liver cancer. Gastroenterology, 2008, 134(2), 379.
[http://dx.doi.org/10.1053/j.gastro.2007.12.037] [PMID: 18242200]
[67]
Drugs Approved for Liver Cancer - National Cancer Institute. Available from: https://www.cancer.gov/about-cancer/treatment/drugs/ liver Accessed 17 May 2021
[68]
Drugs | FDA. Available from: https://www.fda.gov/drugs Accessed 17 May 2021
[69]
Ogawa, M. [Anticancer drugs and pharmacologic actions]. Jpn. J. Clin. Med., 1997, 55(5), 1017-1023.
[PMID: 9155146]
[70]
Kanamaru, R; Wakui, A Mechanism of action of anti-cancer drugs from the viewpoint of RNA metabolism. Cancer Chemother., 1988, 15(4 Pt 2-1), 1011-8.
[71]
Awada, A.; Hendlisz, A.; Gil, T.; Bartholomeus, S.; Mano, M.; de Valeriola, D.; Strumberg, D.; Brendel, E.; Haase, C.G.; Schwartz, B.; Piccart, M. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br. J. Cancer, 2005, 92(10), 1855-1861.
[http://dx.doi.org/10.1038/sj.bjc.6602584] [PMID: 15870716]
[72]
Sorafenib product information. Available from: http://www.univgraph.com/bayer/inserts/sorafenib.pdf
[73]
Roberts, P.J.; Der, C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 2007, 26(22), 3291-3310.
[http://dx.doi.org/10.1038/sj.onc.1210422] [PMID: 17496923]
[74]
Escudier, B.; Eisen, T.; Stadler, W.M.; Szczylik, C.; Oudard, S.; Siebels, M.; Negrier, S.; Chevreau, C.; Solska, E.; Desai, A.A.; Rolland, F.; Demkow, T.; Hutson, T.E.; Gore, M.; Freeman, S.; Schwartz, B.; Shan, M.; Simantov, R.; Bukowski, R.M. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med., 2007, 356(2), 125-134.
[http://dx.doi.org/10.1056/NEJMoa060655] [PMID: 17215530]
[75]
Elser, C.; Siu, L.L.; Winquist, E.; Agulnik, M.; Pond, G.R.; Chin, S.F.; Francis, P.; Cheiken, R.; Elting, J.; McNabola, A.; Wilkie, D.; Petrenciuc, O.; Chen, E.X. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J. Clin. Oncol., 2007, 25(24), 3766-3773.
[http://dx.doi.org/10.1200/JCO.2006.10.2871] [PMID: 17704426]
[76]
Adjei, A.A.; Molina, J.R.; Mandrekar, S.J.; Marks, R.; Reid, J.R.; Croghan, G.; Hanson, L.J.; Jett, J.R.; Xia, C.; Lathia, C.; Simantov, R. Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer. Clin. Cancer Res., 2007, 13(9), 2684-2691.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2889] [PMID: 17473200]
[77]
Haberfeld, H. Austria-codex; ÖsterreichischerApotheke-rverlag: Vienna, Austria, 2015.
[78]
Gupta, A.; Jarzab, B.; Capdevila, J.; Shumaker, R.; Hussein, Z. Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Br. J. Clin. Pharmacol., 2016, 81(6), 1124-1133.
[http://dx.doi.org/10.1111/bcp.12907] [PMID: 26879594]
[79]
Shumaker, R.; Fan, J.; Martinez, G.; Chen, K. Comparative bioavailability study of a 10‐mg capsule and a 10‐mg tablet of lenvatinib (E7080) in healthy subjects. Clin. Pharmacol. Ther., 2012, 91(1), S68.
[80]
Chen, K-F.; Tai, W.T.; Hsu, C.Y.; Huang, J.W.; Liu, C.Y.; Chen, P.J.; Kim, I.; Shiau, C.W. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur. J. Med. Chem., 2012, 55, 220-227.
[http://dx.doi.org/10.1016/j.ejmech.2012.07.023] [PMID: 22871485]
[81]
Capozzi, M.; De Divitiis, C.; Ottaiano, A.; von Arx, C.; Scala, S.; Tatangelo, F.; Delrio, P.; Tafuto, S. Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment. Cancer Manag. Res., 2019, 11, 3847-3860.
[http://dx.doi.org/10.2147/CMAR.S188316] [PMID: 31118801]
[82]
Incio, J.; Tam, J.; Rahbari, N.N.; Suboj, P.; McManus, D.T.; Chin, S.M.; Vardam, T.D.; Batista, A.; Babykutty, S.; Jung, K.; Khachatryan, A.; Hato, T.; Ligibel, J.A.; Krop, I.E.; Puchner, S.B.; Schlett, C.L.; Hoffmman, U.; Ancukiewicz, M.; Shibuya, M.; Carmeliet, P.; Soares, R.; Duda, D.G.; Jain, R.K.; Fukumura, D. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin. Cancer Res., 2016, 22(12), 2993-3004.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1839] [PMID: 26861455]
[83]
Rolny, C.; Mazzone, M.; Tugues, S.; Laoui, D.; Johansson, I.; Coulon, C.; Squadrito, M.L.; Segura, I.; Li, X.; Knevels, E.; Costa, S.; Vinckier, S.; Dresselaer, T.; Åkerud, P.; De Mol, M.; Salomäki, H.; Phillipson, M.; Wyns, S.; Larsson, E.; Buysschaert, I.; Botling, J.; Himmelreich, U.; Van Ginderachter, J.A.; De Palma, M.; Dewerchin, M.; Claesson-Welsh, L.; Carmeliet, P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell, 2011, 19(1), 31-44.
[http://dx.doi.org/10.1016/j.ccr.2010.11.009] [PMID: 21215706]
[84]
Naoum, G.E.; Morkos, M.; Kim, B.; Arafat, W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol. Cancer, 2018, 17(1), 51.
[http://dx.doi.org/10.1186/s12943-018-0786-0] [PMID: 29455653]
[85]
Debaillon, V.A.; Decraecker, M.; Blanc, J.F. Profile of cabozantinib for the treatment of hepatocellular carcinoma: Patient selection and special considerations. J. Hepatocell. Carcinoma, 2020, 7, 91-99.
[http://dx.doi.org/10.2147/JHC.S195570] [PMID: 32607316]
[86]
Lacy, S.A.; Miles, D.R.; Nguyen, L.T. Clinical pharmacokinetics and pharmacodynamics of cabozantinib. Clin. Pharmacokinet., 2017, 56(5), 477-491.
[http://dx.doi.org/10.1007/s40262-016-0461-9] [PMID: 27734291]
[87]
El-Khoueiry, A.B.; Hanna, D.L.; Llovet, J.; Kelley, R.K. Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treat. Rev., 2021, 98102221
[http://dx.doi.org/10.1016/j.ctrv.2021.102221] [PMID: 34029957]
[88]
Gherardi, E.; Birchmeier, W.; Birchmeier, C.; Vande Woude, G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer, 2012, 12(2), 89-103.
[http://dx.doi.org/10.1038/nrc3205] [PMID: 22270953]
[89]
Graham, D.K.; DeRyckere, D.; Davies, K.D.; Earp, H.S. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer, 2014, 14(12), 769-785.
[http://dx.doi.org/10.1038/nrc3847] [PMID: 25568918]
[90]
Akalu, Y.T.; Rothlin, C.V.; Ghosh, S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol. Rev., 2017, 276(1), 165-177.
[http://dx.doi.org/10.1111/imr.12522] [PMID: 28258690]
[91]
Esteban-Fabró, R.; Willoughby, C.E.; Piqué-Gili, M.; Peix, J.; Montironi, C.; Abril-Fornaguera, J.; Torrens, L.; Pinyol, R.; Llovet, J.M. Cabozantinib enhances the efficacy and immune modulatory activity of anti-PD1 therapy in a syngeneic mouse model of hepatocellular carcinoma. J. Hepatol., 2020, 73, S40.
[http://dx.doi.org/10.1016/S0168-8278(20)30632-2]
[92]
Politz, O.; Gruenewald, S.; Walter, A.; Siegel, F.; Scholz, A.; Bender, S.; Kneip, C.; Ellinghaus, P. Rogaratinib, a small molecule pan-FGFR inhibitor potently inhibits FGFR4-phosphorylation and exerts anti-tumor efficacy in vivo and in vitro. Experiment. Mol. Therap., 2018, 4779-4779.
[93]
Zopf, D.; Fichtner, I.; Bhargava, A.; Steinke, W.; Thierauch, K.H.; Diefenbach, K.; Wilhelm, S.; Hafner, F.T.; Gerisch, M. Pharmacologic activity and pharmacokinetics of metabolites of regorafenib in preclinical models. Cancer Med., 2016, 5(11), 3176-3185.
[http://dx.doi.org/10.1002/cam4.883] [PMID: 27734608]
[94]
Kissel, M.; Berndt, S.; Fiebig, L.; Kling, S.; Ji, Q.; Gu, Q.; Lang, T.; Hafner, F.T.; Teufel, M.; Zopf, D. Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma. Oncotarget, 2017, 8(63), 107096-107108.
[http://dx.doi.org/10.18632/oncotarget.22334] [PMID: 29291014]
[95]
Frenette, C.T. The role of regorafenib in hepatocellular carcinoma. Gastroenterol. Hepatol. (N. Y.), 2017, 13(2), 122-124.
[PMID: 28450818]
[96]
Tai, W.T.; Chu, P.Y.; Shiau, C.W.; Chen, Y.L.; Li, Y.S.; Hung, M.H.; Chen, L.J.; Chen, P.L.; Su, J.C.; Lin, P.Y.; Yu, H.C.; Chen, K.F. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma. Clin. Cancer Res., 2014, 20(22), 5768-5776.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0725] [PMID: 25248379]
[97]
Ettrich, T.J.; Seufferlein, T. Regorafenib. Small Molecules in Oncology, 2018, 45-56.
[98]
Peters, G.J.; Backus, H.H.; Freemantle, S.; van Triest, B.; Codacci-Pisanelli, G.; van der Wilt, C.L.; Smid, K.; Lunec, J.; Calvert, A.H.; Marsh, S.; McLeod, H.L.; Bloemena, E.; Meijer, S.; Jansen, G.; van Groeningen, C.J.; Pinedo, H.M. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim. Biophys. Acta, 2002, 1587(2-3), 194-205.
[http://dx.doi.org/10.1016/S0925-4439(02)00082-0] [PMID: 12084461]
[99]
Reigner, B.; Blesch, K.; Weidekamm, E. Clinical pharmacokinetics of capecitabine. Clin. Pharmacokinet., 2001, 40(2), 85-104.
[http://dx.doi.org/10.2165/00003088-200140020-00002] [PMID: 11286326]
[100]
Mini, E.; Nobili, S.; Caciagli, B.; Landini, I.; Mazzei, T. Cellular pharmacology of gemcitabine. Ann. Oncol., 2006, 17(Suppl. 5), v7-v12.
[http://dx.doi.org/10.1093/annonc/mdj941] [PMID: 16807468]
[101]
Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Shahar Yar, M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem., 2017, 125, 143-189.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.023] [PMID: 27662031]
[102]
Ahmed, N.M.; Youns, M.; Soltan, M.K.; Said, A.M. Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1110-1120.
[http://dx.doi.org/10.1080/14756366.2019.1612889] [PMID: 31117890]
[103]
Chen, F.; Fang, Y.; Zhao, R.; Le, J.; Zhang, B.; Huang, R.; Chen, Z.; Shao, J. Evolution in medicinal chemistry of sorafenib derivatives for hepatocellular carcinoma. Eur. J. Med. Chem., 2019, 179, 916-935.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.070] [PMID: 31306818]
[104]
Gauthier, A.; Ho, M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol. Res., 2013, 43(2), 147-154.
[http://dx.doi.org/10.1111/j.1872-034X.2012.01113.x] [PMID: 23145926]
[105]
Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov., 2006, 5(10), 835-844.
[http://dx.doi.org/10.1038/nrd2130] [PMID: 17016424]
[106]
Wan, P.T.C. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 2004, 116(6), 855-867.
[http://dx.doi.org/10.1016/S0092-8674(04)00215-6]
[107]
Zhang, J.; Yang, P.L.; Gray, N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer, 2009, 9(1), 28-39.
[http://dx.doi.org/10.1038/nrc2559] [PMID: 19104514]
[108]
Hwang, S.H.; Wecksler, A.T.; Zhang, G.; Morisseau, C.; Nguyen, L.V.; Fu, S.H.; Hammock, B.D. Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors. Bioorg. Med. Chem. Lett., 2013, 23(13), 3732-3737.
[http://dx.doi.org/10.1016/j.bmcl.2013.05.011] [PMID: 23726028]
[109]
Okamoto, K.; Kodama, K.; Takase, K.; Sugi, N.H.; Yamamoto, Y.; Iwata, M.; Tsuruoka, A. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett., 2013, 340(1), 97-103.
[http://dx.doi.org/10.1016/j.canlet.2013.07.007] [PMID: 23856031]
[110]
Casak, S.J.; Donoghue, M.; Fashoyin-Aje, L.; Jiang, X.; Rodriguez, L.; Shen, Y.L.; Xu, Y.; Jiang, X.; Liu, J.; Zhao, H.; Pierce, W.F.; Mehta, S.; Goldberg, K.B.; Theoret, M.R.; Kluetz, P.G.; Pazdur, R.; Lemery, S.J. FDA approval summary: Atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin. Cancer Res., 2021, 27(7), 1836-1841.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-3407] [PMID: 33139264]
[111]
Dipasquale, A.; Marinello, A.; Santoro, A. A comparison of lenvatinib versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma: selection criteria to guide physician’s choice in a new therapeutic scenario. J. Hepatocell. Carcinoma, 2021, 8, 241-251.
[http://dx.doi.org/10.2147/JHC.S270532] [PMID: 33884259]
[112]
Kudo, M. Cabozantinib as a second-line agent in advanced hepatocellular carcinoma. Liver Cancer, 2018, 7(2), 123-133.
[http://dx.doi.org/10.1159/000488542] [PMID: 29888203]
[113]
Martins, P.; Rosa, D.R.; Fernandes, A.; Baptista, P.V. Nanoparticle drug delivery systems: recent patents and applications in nanomedicine. Recent Pat. Nanomed., 2013, 3(2), 105-118.
[http://dx.doi.org/10.2174/1877912304666140304000133]
[114]
Kumar, S.; Narasimhan, B. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chem. Cent. J., 2018, 12(1), 38.
[http://dx.doi.org/10.1186/s13065-018-0406-5] [PMID: 29619583]
[115]
Sagnella, S.M.; McCarroll, J.A.; Kavallaris, M. Drug delivery: beyond active tumour targeting. Nanomedicine, 2014, 10(6), 1131-1137.
[http://dx.doi.org/10.1016/j.nano.2014.04.012] [PMID: 24823644]
[116]
Wicki, A.; Witzigmann, D.; Balasubramanian, V.; Huwyler, J. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J. Control. Release, 2015, 200, 138-157.
[http://dx.doi.org/10.1016/j.jconrel.2014.12.030] [PMID: 25545217]
[117]
Martins, P.; Jesus, J.; Santos, S.; Raposo, L.R.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R. Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules, 2015, 20(9), 16852-16891.
[http://dx.doi.org/10.3390/molecules200916852] [PMID: 26389876]
[118]
Khemapech, N.; Oranratanaphan, S.; Termrungruanglert, W.; Lertkhachonsuk, R.; Vasurattana, A. Salvage chemotherapy in recurrent platinum-resistant or refractory epithelial ovarian cancer with Carboplatin and distearoylphosphatidylcholine pegylated liposomal Doxorubicin (lipo-dox®). Asian Pac. J. Cancer Prev., 2013, 14(3), 2131-2135.
[http://dx.doi.org/10.7314/APJCP.2013.14.3.2131] [PMID: 23679331]
[119]
Batist, G.; Ramakrishnan, G.; Rao, C.S.; Chandrasekharan, A.; Gutheil, J.; Guthrie, T.; Shah, P.; Khojasteh, A.; Nair, M.K.; Hoelzer, K.; Tkaczuk, K.; Park, Y.C.; Lee, L.W. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J. Clin. Oncol., 2001, 19(5), 1444-1454.
[http://dx.doi.org/10.1200/JCO.2001.19.5.1444] [PMID: 11230490]
[120]
Hanaoka, H.; Nakajima, T.; Sato, K.; Watanabe, R.; Phung, Y.; Gao, W.; Harada, T.; Kim, I.; Paik, C.H.; Choyke, P.L.; Ho, M.; Kobayashi, H. Photoimmunotherapy of hepatocellular carcinoma-targeting Glypican-3 combined with nanosized albumin-bound paclitaxel. Nanomedicine (Lond.), 2015, 10(7), 1139-1147.
[http://dx.doi.org/10.2217/nnm.14.194] [PMID: 25929570]

Rights & Permissions Print Cite
Article Metrics
3
© 2024 Bentham Science Publishers | Privacy Policy