Recent Advances in PI3 Kinase Inhibitors: Anticancer Activities and
Structure-Activity Relationships

Vivek      Asati; Arjun      Anant; Debarshi   Kar   Mahapatra; Sanjay   Kumar   Bharti

doi:10.2174/1389450123666220202154757

Abstract

Phosphatidyl-inositol-3-kinase (PI3K) has emerged as a potential therapeutic target for the development of novel anticancer drugs. The dysregulation of PI3K has been associated with many human malignancies such as breast, colon, endometrial, brain, and prostate cancers. The PI3K kinases in their different isoforms, namely α, β, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for the therapeutic failure of current therapeutics. Recently, various PI3K signaling pathway inhibitors have been identified, which showed promising therapeutic results by acting on specific isoforms of the kinase too. Several inhibitors containing medicinally privileged scaffolds like oxadiazole, pyrrolotriazine, quinazoline, quinazolinone, quinazoline-chalcone hybrids, quinazoline-sulfonamide, pyrazolochalcone, quinolone hydroxamic acid, benzofuropyridinone, imidazopyridine, benzoxazines, dibenzoxanthene, indoloderivatives, benzimidazole, and benzothiazine derivatives have been developed to target the PI3K pathway and/or a specific isoform. The PI3K inhibitors under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights, anticancer activities, and structure-activity relationship (SARs) studies of recent PI3K inhibitors, including their clinical stages of development and therapeutic values.

Keywords: PI3K, proliferation, kinase, anticancer agents, signaling pathways, SAR.

« Previous Next »

Graphical Abstract

[1] 
Maffucci, T.; Falasca, M. Inositol polyphosphate-based compounds as inhibitors of phosphoinositide 3-kinase-dependent signaling. Int. J. Mol. Sci.,  2020, 21(19), 7198.
[http://dx.doi.org/10.3390/ijms21197198] [PMID:  33003448] 
[2] 
Backer, J.M. The regulation and function of Class III PI3Ks: Novel roles for Vps34. Biochem. J.,  2008, 410(1), 1-17.
[http://dx.doi.org/10.1042/BJ20071427] [PMID:  18215151] 
[3] 
Arcaro, A.; Guerreiro, A.S. The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr. Genomics,  2007, 8(5), 271-306.
[http://dx.doi.org/10.2174/138920207782446160] [PMID:  19384426] 
[4] 
Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.; Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol.,  2010, 11(5), 329-341.
[http://dx.doi.org/10.1038/nrm2882] [PMID:  20379207] 
[5] 
Okkenhaug, K.; Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol.,  2003, 3(4), 317-330.
[http://dx.doi.org/10.1038/nri1056] [PMID:  12669022] 
[6] 
Zhang, X.; Tang, N.; Hadden, T.J.; Rishi, A.K. Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta,  2011, 1813(11), 1978-1986.
[http://dx.doi.org/10.1016/j.bbamcr.2011.03.010] [PMID:  21440011] 
[7] 
Powis, G.; Bonjouklian, R.; Berggren, M.M.; Gallegos, A.; Abraham, R.; Ashendel, C.; Zalkow, L.; Matter, W.F.; Dodge, J.; Grindey, G.; Vlahos, C.J. Wortmannin, a potent and selective inhibitor  of phosphatidylinositol-3-kinase Cancer Res.,  1994, 54(9), 2419-2423.
[PMID:  8162590] 
[8] 
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.
[http://dx.doi.org/10.1016/S0021-9258(17)37680-9] [PMID:  8106507] 
[9] 
Friedman, L. GDC-0941, a potent, selective, orally bioavailable inhibitor of class I PI3K. Cancer Res.,  2008, 68, LB-110.
[10] 
Ehrhardt, M.; Craveiro, R.B.; Holst, M.I.; Pietsch, T.; Dilloo, D. The PI3K inhibitor GDC- 0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy. Oncotarget,  2015, 6, 802-813.
[http://dx.doi.org/10.18632/oncotarget.2742] 
[11] 
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] 
[12] 
Liu, T-J.; Koul, D.; LaFortune, T.; Tiao, N.; Shen, R.J.; Maira, S-M.; Garcia-Echevrria, C.; Yung, W.K.A. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol. Cancer Ther.,  2009, 8(8), 2204-2210.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0160] [PMID:  19671762] 
[13] 
Maira, S.M. PI3K inhibitors for cancer treatment: Five years of preclinical and clinical research after BEZ235. Mol. Cancer Ther.,  2011, 10(11), 2016.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0792] [PMID:  22072802] 
[14] 
Raynaud, F.I.; Eccles, S.A.; Patel, S.; Alix, S.; Box, G.; Chuckowree, I.; Folkes, A.; Gowan, S.; De Haven Brandon, A.; Di Stefano, F.; Hayes, A.; Henley, A.T.; Lensun, L.; Pergl-Wilson, G.; Robson, A.; Saghir, N.; Zhyvoloup, A.; McDonald, E.; Sheldrake, P.; Shuttleworth, S.; Valenti, M.; Wan, N.C.; Clarke, P.A.; Workman, P. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: From PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther.,  2009, 8(7), 1725-1738.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-1200] [PMID:  19584227] 
[15] 
Fruman, D.A.; Rommel, C. PI3K and cancer: Lessons, challenges and opportunities. Nat. Rev. Drug Discov.,  2014, 13(2), 140-156.
[http://dx.doi.org/10.1038/nrd4204] [PMID:  24481312] 
[16] 
Lannutti, B.J.; Meadows, S.A.; Herman, S.E.; Kashishian, A.; Steiner, B.; Johnson, A.J.; Byrd, J.C.; Tyner, J.W.; Loriaux, M.M.; Deininger, M.; Druker, B.J.; Puri, K.D.; Ulrich, R.G.; Giese, N.A. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood,  2011, 117(2), 591-594.
[http://dx.doi.org/10.1182/blood-2010-03-275305] [PMID:  20959606] 
[17] 
Furet, P.; Guagnano, V.; Fairhurst, R.A.; Imbach-Weese, P.; Bruce, I.; Knapp, M.; Fritsch, C.; Blasco, F.; Blanz, J.; Aichholz, R.; Hamon, J.; Fabbro, D.; Caravatti, G. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett.,  2013, 23(13), 3741-3748.
[http://dx.doi.org/10.1016/j.bmcl.2013.05.007] [PMID:  23726034] 
[18] 
Fritsch, C.; Huang, A.; Chatenay-Rivauday, C.; Schnell, C.; Reddy, A.; Liu, M.; Kauffmann, A.; Guthy, D.; Erdmann, D.; De Pover, A.; Furet, P.; Gao, H.; Ferretti, S.; Wang, Y.; Trappe, J.; Brachmann, S.M.; Maira, S.M.; Wilson, C.; Boehm, M.; Garcia-Echeverria, C.; Chene, P.; Wiesmann, M.; Cozens, R.; Lehar, J.; Schlegel, R.; Caravatti, G.; Hofmann, F.; Sellers, W.R. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther.,  2014, 13(5), 1117-1129.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0865] [PMID:  24608574] 
[19] 
Zumsteg, Z.S.; Morse, N.; Krigsfeld, G.; Gupta, G.; Higginson, D.S.; Lee, N.Y.; Morris, L.; Ganly, I.; Shiao, S.L.; Powell, S.N.; Chung, C.H.; Scaltriti, M.; Baselga, J. Taselisib (GDC-0032), a potent β-sparing small molecule inhibitor of PI3K, radiosensitizes head and neck squamous carcinomas containing activating PIK3CA alterations. Clin. Cancer Res.,  2016, 22(8), 2009-2019.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2245] [PMID:  26589432] 
[20] 
Ndubaku, C.O.; Heffron, T.P.; Staben, S.T.; Baumgardner, M.; Blaquiere, N.; Bradley, E.; Bull, R.; Do, S.; Dotson, J.; Dudley, D.; Edgar, K.A.; Friedman, L.S.; Goldsmith, R.; Heald, R.A.; Kolesnikov, A.; Lee, L.; Lewis, C.; Nannini, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W.W.; Salphati, L.; Sideris, S.; Wallin, J.J.; Wang, L.; Wei, B.; Sampath, D.; Olivero, A.G. 
                        Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4] oxazepin-9-yl]-1H-pyrazol-1-yl}-2- methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust 
                        in vivo
                         antitumor activity.
                     J. Med. Chem.,  2013, 56, 4597-4610.
[http://dx.doi.org/10.1021/jm4003632] [PMID:  23662903] 
[21] 
Jessen, K.A.; Kessler, L.; Kucharski, J.; Guo, X.; Staunton, J.; Elia, M.; Janes, M.; Lan, L.; Wang, S.; Stewart, J.; Darjania, L.; Li, L.; Chan, K.; Martin, M.; Ren, P.; Fruman, D.; Rommel, C.; Liu, Y. Abstract 4501: INK1117: A potent and orally efficacious PI3Kα-selective inhibitor for the treatment of cancer. Cancer Res.,  2011, 71, 4501.
[http://dx.doi.org/10.1158/1538-7445.AM2011-4501] 
[22] 
Barlaam, B.; Cosulich, S.; Degorce, S.; Fitzek, M.; Green, S.; Hancox, U.; Lambert-van der Brempt, C.; Lohmann, J.J.; Maudet, M.; Morgentin, R.; Pasquet, M.J.; Péru, A.; Plé, P.; Saleh, T.; Vautier, M.; Walker, M.; Ward, L.; Warin, N. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers. J. Med. Chem.,  2015, 58(2), 943-962.
[http://dx.doi.org/10.1021/jm501629p] [PMID:  25514658] 
[23] 
Fjellstrom, O.; Gustafsson, D.; Jackson, S.; Lindberg, J.A. Enantiomerically
pure (-) 2-[1-(7- methyl-2-(morpholin-4-yl)-4-oxo-4hpyrido[
1,2-a]pyrimidin-9-yl)ethylamino]benzoic acid, its use in
medical therapy, and a pharmaceutical composition comprising it -
026. US-2009191177-A1, 2009.
[24] 
Liu, N.; Rowley, B.R.; Bull, C.O.; Schneider, C.; Haegebarth, A.; Schatz, C.A.; Fracasso, P.R.; Wilkie, D.P.; Hentemann, M.; Wilhelm, S.M.; Scott, W.J.; Mumberg, D.; Ziegelbauer, K. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol. Cancer Ther.,  2013, 12(11), 2319-2330.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0993-T] [PMID:  24170767] 
[25] 
Martínez González, S.; Hernández, A.I.; Álvarez, R.M.; Rodríguez, A.; Ramos-Lima, F.; Bischoff, J.R.; Albarrán, M.I.; Cebriá, A.; Hernández-Encinas, E.; García-Arocha, J.; Cebrián, D.; Blanco-Aparicio, C.; Pastor, J. Identification of novel PI3K inhibitors through a scaffold hopping strategy. Bioorg. Med. Chem. Lett.,  2017, 27(21), 4794-4799.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.059] [PMID:  29017786] 
[26] 
Kai, W.; Yating, S.; Lin, M.; Kaiyong, Y.; Baojin, H.; Wu, Y.; Fangzhou, Y.; Yan, C. Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor. Biochem. Pharmacol.,  2018, 152, 153-164.
[http://dx.doi.org/10.1016/j.bcp.2018.03.022] [PMID:  29574068] 
[27] 
Salahuddin; Mazumder, A.; Shaharyar, M. Synthesis, characterization, and in vitro anticancer evaluation of novel 2,5-disubstituted 1,3,4-oxadiazole analogue. BioMed Res. Int.,  2014, 2014, 491492.
[http://dx.doi.org/10.1155/2014/491492] [PMID:  25177693] 
[28] 
Dugar, S.; Hollinger, F.P.; Kuila, B.; Arora, R.; Sen, S.; Mahajan, D. Synthesis and evaluation of pyrrolotriazine based molecules as PI3 kinase inhibitors. Bioorg. Med. Chem. Lett.,  2015, 25(16), 3142-3146.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.007] [PMID:  26112437] 
[29] 
Hei, Y.Y.; Xin, M.; Zhang, H.; Xie, X.X.; Mao, S.; Zhang, S.Q. Synthesis and antitumor activity evaluation of 4,6-disubstituted quinazoline derivatives as novel PI3K inhibitors. Bioorg. Med. Chem. Lett.,  2016, 26(18), 4408-4413.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.015] [PMID:  27544401] 
[30] 
Jafari, E.; Khajouei, M.R.; Hassanzadeh, F.; Hakimelahi, G.H.; Khodarahmi, G.A. Quinazolinone and quinazoline derivatives: Recent structures with potent antimicrobial and cytotoxic activities. Res. Pharm. Sci.,  2016, 11(1), 1-14.
[PMID:  27051427] 
[31] 
Wang, X.M.; Xin, M.H.; Xu, J.; Kang, B.R.; Li, Y.; Lu, S.M.; Zhang, S.Q. 
                        Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides 
                        in vitro
                         and 
                        in vivo
                        .
                     Eur. J. Med. Chem.,  2015, 96, 382-395.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.037] [PMID:  25911625] 
[32] 
Zhang, H.; Xin, M.H.; Xie, X.X.; Mao, S.; Zuo, S.J.; Lu, S.M.; Zhang, S.Q. Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety. Bioorg. Med. Chem.,  2015, 23(24), 7765-7776.
[http://dx.doi.org/10.1016/j.bmc.2015.11.027] [PMID:  26652969] 
[33] 
Abbas, S.H.; Abd El-Hafeez, A.A.; Shoman, M.E.; Montano, M.M.; Hassan, H.A. New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity. Bioorg. Chem.,  2019, 82, 360-377.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.064] [PMID:  30428415] 
[34] 
Blanco, B.; Herrero-Sánchez, C.; Rodríguez-Serrano, C.; Sánchez-Barba, M.; Del Cañizo, M.C. Comparative effect of two pan-class I PI3K inhibitors used as anticancer drugs on human T cell function. Int. Immunopharmacol.,  2015, 28(1), 675-685.
[http://dx.doi.org/10.1016/j.intimp.2015.07.032] [PMID:  26256696] 
[35] 
Chen, Y.; Zhang, L.; Yang, C.; Han, J.; Wang, C.; Zheng, C.; Zhou, Y.; Lv, J.; Song, Y.; Zhu, J. 
                        Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with 
                        in vivo
                         efficacies against hepatocellular carcinoma.
                     Bioorg. Med. Chem.,  2016, 24(5), 957-966.
[http://dx.doi.org/10.1016/j.bmc.2016.01.008] [PMID:  26819001] 
[36] 
Gao, G.R.; Liu, J.L.; Mei, D.S.; Ding, J.; Meng, L.H.; Duan, W.H. Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors. Chin. Chem. Lett.,  2015, 26, 118-120.
[http://dx.doi.org/10.1016/j.cclet.2014.10.016] 
[37] 
Lv, X.; Ying, H.; Ma, X.; Qiu, N.; Wu, P.; Yang, B.; Hu, Y. Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors. Eur. J. Med. Chem.,  2015, 99, 36-50.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.025] [PMID:  26046312] 
[38] 
Shaik, A.B.; Rao, G.K.; Kumar, G.B.; Patel, N.; Reddy, V.S.; Khan, I.; Routhu, S.R.; Kumar, C.G.; Veena, I.; Chandra Shekar, K.; Barkume, M.; Jadhav, S.; Juvekar, A.; Kode, J.; Pal-Bhadra, M.; Kamal, A. Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells. Eur. J. Med. Chem.,  2017, 139, 305-324.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.056] [PMID:  28803046] 
[39] 
Thakur, A.; Tawa, G.J.; Henderson, M.J.; Danchik, C.; Liu, S.; Shah, P.; Wang, A.Q.; Dunn, G.; Kabir, M.; Padilha, E.C.; Xu, X.; Simeonov, A.; Kharbanda, S.; Stone, R.; Grewal, G. Design, synthesis, and biological evaluation of quinazolin-4-one-based hydroxamic acids as dual PI3K/HDAC inhibitors. J. Med. Chem.,  2020, 63(8), 4256-4292.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00193] [PMID:  32212730] 
[40] 
Ding, H.W.; Wang, S.; Qin, X.C.; Wang, J.; Song, H.R.; Zhao, Q.C.; Song, S.J. Design, synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors. Bioorg. Med. Chem.,  2019, 27(13), 2729-2740.
[http://dx.doi.org/10.1016/j.bmc.2019.04.024] [PMID:  31097403] 
[41] 
Zhang, K.; Lai, F.; Lin, S.; Ji, M.; Zhang, J.; Zhang, Y.; Jin, J.; Fu, R.; Wu, D.; Tian, H.; Xue, N.; Sheng, L.; Zou, X.; Li, Y.; Chen, X.; Xu, H. Design, synthesis, and biological evaluation of 4-methyl quinazoline derivatives as anticancer agents simultaneously targeting phosphoinositide 3-kinases and histone deacetylases. J. Med. Chem.,  2019, 62(15), 6992-7014.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00390] [PMID:  31117517] 
[42] 
Zhang, J.; Lv, X.; Ma, X.; Hu, Y. Discovery of a series of N-(5-(quinolin-6-yl) pyridin-3-yl) benzenesulfonamides as PI3K/mTOR dual inhibitors. Eur. J. Med. Chem.,  2017, 127, 509-520.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.016] 
[43] 
Li, L.; Zhang, C.L.; Song, H.R.; Tan, C.Y.; Ding, H.W.; Jiang, Y.Y. Discovery of novel dual inhibitors of VEGFR and PI3K kinases containing 2-ureidothiazole scaffold. Chin. Chem. Lett.,  2016, 27, 1-6.
[http://dx.doi.org/10.1016/j.cclet.2015.09.008] 
[44] 
Liu, L.; Shi, B.; Li, X.; Wang, X.; Lu, X.; Cai, X.; Huang, A.; Luo, G.; You, Q.; Xiang, H. Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ. Bioorg. Med. Chem.,  2018, 26(15), 4537-4543.
[http://dx.doi.org/10.1016/j.bmc.2018.07.047] [PMID:  30077608] 
[45] 
Yu, Y.; Han, Y.; Zhang, F.; Gao, Z.; Zhu, T.; Dong, S.; Ma, M. Design, synthesis, and biological evaluation of imidazo [1, 2-a] pyridine derivatives as novel PI3K/mTOR dual inhibitors. J. Med. Chem.,  2020, 63(6), 3028-3046.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01736] [PMID:  32069401] 
[46] 
Morrison, R.; Al-Rawi, J.M.; Jennings, I.G.; Thompson, P.E.; Angove, M.J. Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines. Eur. J. Med. Chem.,  2016, 110, 326-339.
[http://dx.doi.org/10.1016/j.ejmech.2016.01.042] [PMID:  26854431] 
[47] 
Khan, M.I.; Momeny, M.; Ostadhadi, S.; Jahanabadi, S.; Ejtemaei-Mehr, S.; Sameem, B.; Zarrinrad, G.; Dehpour, A.R. Thalidomide attenuates development of morphine dependence in mice by inhibiting PI3K/Akt and nitric oxide signaling pathways. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2018, 82, 39-48.
[http://dx.doi.org/10.1016/j.pnpbp.2017.12.002] [PMID:  29223784] 
[48] 
Wang, X.Z.; Jia, Z.; Yang, H.H.; Liu, Y.J. Dibenzoxanthenes induce apoptosis and autophagy in HeLa cells by modeling the PI3K/Akt pathway. J. Photochem. Photobiol. B,  2018, 187, 76-88.
[http://dx.doi.org/10.1016/j.jphotobiol.2018.08.001] [PMID:  30099272] 
[49] 
Yadav, R.R.; Guru, S.K.; Joshi, P.; Mahajan, G.; Mintoo, M.J.; Kumar, V.; Bharate, S.S.; Mondhe, D.M.; Vishwakarma, R.A.; Bhushan, S.; Bharate, S.B. 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors. Eur. J. Med. Chem.,  2016, 122, 731-743.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.006] [PMID:  27479483] 
[50] 
Yu, Z.; Chen, Z.; Su, Q.; Ye, S.; Yuan, H.; Kuai, M.; Lv, M.; Tu, Z.; Yang, X.; Liu, R.; Hu, G.; Li, Q. Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives. Bioorg. Med. Chem.,  2019, 27(6), 944-954.
[http://dx.doi.org/10.1016/j.bmc.2019.01.028] [PMID:  30777660] 
[51] 
Ding, H.W.; Yu, L.; Bai, M.X.; Qin, X.C.; Song, M.T.; Zhao, Q.C. Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents. Bioorg. Chem.,  2019, 93, 103283.
[http://dx.doi.org/10.1016/j.bioorg.2019.103283] [PMID:  31585260] 
[52] 
Zhang, Q.; Zhou, L.; Guan, Y.; Cheng, Y.; Han, X. BENC-511, a novel PI3K inhibitor, suppresses metastasis of non-small cell lung cancer cells by modulating β-catenin/ZEB1 regulatory loop. Chem. Biol. Interact.,  2018, 294, 18-27.
[http://dx.doi.org/10.1016/j.cbi.2018.08.010] [PMID:  30125547] 
[53] 
Gong, Y.P.; Tang, L.Q.; Liu, T.S.; Liu, Z.P. Synthesis and evaluation of novel 2H-Benzo[e]-[1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. Molecules,  2019, 24(23), 4299.
[http://dx.doi.org/10.3390/molecules24234299] [PMID:  31775363] 
[54] 
Fan, Y.; Ding, H.; Kim, D.; Bach, D.H.; Hong, J.Y.; Xu, Y.; Lee, S.K. Antitumor activity of DFX117 by dual inhibition of c-Met and PI3Kα in non-small cell lung cancer. Cancers (Basel),  2019, 11(5), 627.
[http://dx.doi.org/10.3390/cancers11050627] [PMID:  31060329] 
[55] 
U.S. National Library of Medicine   Available from:
                    https://clinicaltrials.gov/ct2/home (Accessed on: 12/04/2020).

Rights & Permissions Print Cite

Article Metrics

25

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1389450123666220202154757	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607

Mini-Reviews in Medicinal Chemistry

Recent Advances in PI3 Kinase Inhibitors: Anticancer Activities and Structure-Activity Relationships

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract