Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Mini-Review Article

Structure-based Drug Design Strategies in the Development of Small Molecule Inhibitors Targeting Bcl-2 Family Proteins

Author(s): Zhe Yin, Donglin Yang, Jun Wang and Yuequan Jiang*

Volume 17, Issue 8, 2020

Page: [943 - 953] Pages: 11

DOI: 10.2174/1570180817666200213114759

open access plus

Abstract

Proteins of B-cell lymphoma (Bcl-2) family are key regulators of apoptosis and are involved in the pathogenesis of various cancers. Disrupting the interactions between the antiapoptotic and proapoptotic Bcl-2 members is an attractive strategy to reactivate the apoptosis of cancer cells. Structure-based drug design (SBDD) has been successfully applied to the discovery of small molecule inhibitors targeting Bcl-2 proteins in past decades. Up to now, many Bcl-2 inhibitors with different paralogue selectivity profiles have been developed and some were used in clinical trials. This review focused on the recent applications of SBDD strategies in the development of small molecule inhibitors targeting Bcl-2 family proteins.

Keywords: Bcl-2 family proteins, apoptosis, cancer, structure-based drug design strategy, co-crystal structure, small molecule inhibitors.

« Previous Next »
Graphical Abstract

[1]
Portt, L.; Norman, G.; Clapp, C.; Greenwood, M.; Greenwood, M.T. Anti-apoptosis and cell survival: a review. Biochim. Biophys. Acta, 2011, 1813(1), 238-259.
[http://dx.doi.org/10.1016/j.bbamcr.2010.10.010] [PMID: 20969895]
[2]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[3]
Fesik, S.W. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer, 2005, 5(11), 876-885.
[http://dx.doi.org/10.1038/nrc1736] [PMID: 16239906]
[4]
Hardwick, J.M.; Soane, L. Multiple functions of BCL-2 family proteins. Cold Spring Harb. Perspect. Biol., 2013, 5(2)a008722
[http://dx.doi.org/10.1101/cshperspect.a008722] [PMID: 23378584]
[5]
Huang, D.C.; Strasser, A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell, 2000, 103(6), 839-842.
[http://dx.doi.org/10.1016/S0092-8674(00)00187-2] [PMID: 11136969]
[6]
Dewson, G.; Kluck, R.M. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J. Cell Sci., 2009, 122(Pt 16), 2801-2808.
[http://dx.doi.org/10.1242/jcs.038166] [PMID: 19795525]
[7]
Yap, J.L.; Chen, L.; Lanning, M.E.; Fletcher, S. Expanding the cancer arsenal with targeted therapies: disarmament of the antiapoptotic bcl-2 proteins by small molecules. J. Med. Chem., 2017, 60(3), 821-838.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01888] [PMID: 27749061]
[8]
Adams, J.M.; Cory, S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr. Opin. Immunol., 2007, 19(5), 488-496.
[http://dx.doi.org/10.1016/j.coi.2007.05.004] [PMID: 17629468]
[9]
Sattler, M.; Liang, H.; Nettesheim, D.; Meadows, R.P.; Harlan, J.E.; Eberstadt, M.; Yoon, H.S.; Shuker, S.B.; Chang, B.S.; Minn, A.J.; Thompson, C.B.; Fesik, S.W. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science, 1997, 275(5302), 983-986.
[http://dx.doi.org/10.1126/science.275.5302.983] [PMID: 9020082]
[10]
Petros, A.M.; Nettesheim, D.G.; Wang, Y.; Olejniczak, E.T.; Meadows, R.P.; Mack, J.; Swift, K.; Matayoshi, E.D.; Zhang, H.; Thompson, C.B.; Fesik, S.W. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci., 2000, 9, 2528-2534.
[PMID: 11206074]
[11]
Liu, X.; Dai, S.; Zhu, Y.; Marrack, P.; Kappler, J.W. The structure of a Bcl-xL/Bim fragment complex: implications for Bim function. Immunity, 2003, 19(3), 341-352.
[http://dx.doi.org/10.1016/S1074-7613(03)00234-6] [PMID: 14499110]
[12]
Czabotar, P.E.; Lee, E.F.; van Delft, M.F.; Day, C.L.; Smith, B.J.; Huang, D.C.; Fairlie, W.D.; Hinds, M.G.; Colman, P.M. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc. Natl. Acad. Sci. USA, 2007, 104(15), 6217-6222.
[http://dx.doi.org/10.1073/pnas.0701297104] [PMID: 17389404]
[13]
Huang, Z. Bcl-2 family proteins as targets for anticancer drug design. Oncogene, 2000, 19(56), 6627-6631.
[http://dx.doi.org/10.1038/sj.onc.1204087] [PMID: 11426648]
[14]
Xiao, G.; Fang, H.; Xing, C.; Xu, W. Structure, function and inhibition of Bcl-2 family proteins: a new target for anti-tumor agents. Mini Rev. Med. Chem., 2009, 9(14), 1596-1604.
[http://dx.doi.org/10.2174/138955709791012238] [PMID: 20236080]
[15]
Lessene, G.; Czabotar, P.E.; Colman, P.M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov., 2008, 7(12), 989-1000.
[http://dx.doi.org/10.1038/nrd2658] [PMID: 19043450]
[16]
Youle, R.J.; Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol., 2008, 9(1), 47-59.
[http://dx.doi.org/10.1038/nrm2308] [PMID: 18097445]
[17]
Punnoose, E.A.; Leverson, J.D.; Peale, F.; Boghaert, E.R.; Belmont, L.D.; Tan, N.; Young, A.; Mitten, M.; Ingalla, E.; Darbonne, W.C.; Oleksijew, A.; Tapang, P.; Yue, P.; Oeh, J.; Lee, L.; Maiga, S.; Fairbrother, W.J.; Amiot, M.; Souers, A.J.; Sampath, D. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the bcl-2 selective antagonist venetoclax in multiple myeloma models. Mol. Cancer Ther., 2016, 15(5), 1132-1144.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0730] [PMID: 26939706]
[18]
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]
[19]
Petros, A.M.; Dinges, J.; Augeri, D.J.; Baumeister, S.A.; Betebenner, D.A.; Bures, M.G.; Elmore, S.W.; Hajduk, P.J.; Joseph, M.K.; Landis, S.K.; Nettesheim, D.G.; Rosenberg, S.H.; Shen, W.; Thomas, S.; Wang, X.; Zanze, I.; Zhang, H.; Fesik, S.W. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J. Med. Chem., 2006, 49(2), 656-663.
[http://dx.doi.org/10.1021/jm0507532] [PMID: 16420051]
[20]
Wendt, M.D.; Shen, W.; Kunzer, A.; McClellan, W.J.; Bruncko, M.; Oost, T.K.; Ding, H.; Joseph, M.K.; Zhang, H.; Nimmer, P.M.; Ng, S.C.; Shoemaker, A.R.; Petros, A.M.; Oleksijew, A.; Marsh, K.; Bauch, J.; Oltersdorf, T.; Belli, B.A.; Martineau, D.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W. Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J. Med. Chem., 2006, 49(3), 1165-1181.
[http://dx.doi.org/10.1021/jm050754u] [PMID: 16451081]
[21]
Bruncko, M.; Oost, T.K.; Belli, B.A.; Ding, H.; Joseph, M.K.; Kunzer, A.; Martineau, D.; McClellan, W.J.; Mitten, M.; Ng, S.C.; Nimmer, P.M.; Oltersdorf, T.; Park, C.M.; Petros, A.M.; Shoemaker, A.R.; Song, X.; Wang, X.; Wendt, M.D.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J. Med. Chem., 2007, 50(4), 641-662.
[http://dx.doi.org/10.1021/jm061152t] [PMID: 17256834]
[22]
Lee, E.F.; Czabotar, P.E.; Smith, B.J.; Deshayes, K.; Zobel, K.; Colman, P.M.; Fairlie, W.D. Crystal structure of ABT-737 complexed with Bcl-xL: implications for selectivity of antagonists of the Bcl-2 family. Cell Death Differ., 2007, 14(9), 1711-1713.
[http://dx.doi.org/10.1038/sj.cdd.4402178] [PMID: 17572662]
[23]
The Discovery of Navitoclax, a Bcl-2 Family Inhibitor. In: Wendt M. (eds) Protein-Protein Interactions. Topics in Medicinal Chemistry, vol 8. Springer, Berlin, Heidelber. 2012, 8, 231-258.
[http://dx.doi.org/10.1007/978-3-642-28965-1_7]
[24]
Park, C.M.; Bruncko, M.; Adickes, J.; Bauch, J.; Ding, H.; Kunzer, A.; Marsh, K.C.; Nimmer, P.; Shoemaker, A.R.; Song, X.; Tahir, S.K.; Tse, C.; Wang, X.; Wendt, M.D.; Yang, X.; Zhang, H.; Fesik, S.W.; Rosenberg, S.H.; Elmore, S.W. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J. Med. Chem., 2008, 51(21), 6902-6915.
[http://dx.doi.org/10.1021/jm800669s] [PMID: 18841882]
[25]
Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; Huang, D.C.; Hymowitz, S.G.; Jin, S.; Khaw, S.L.; Kovar, P.J.; Lam, L.T.; Lee, J.; Maecker, H.L.; Marsh, K.C.; Mason, K.D.; Mitten, M.J.; Nimmer, P.M.; Oleksijew, A.; Park, C.H.; Park, C.M.; Phillips, D.C.; Roberts, A.W.; Sampath, D.; Seymour, J.F.; Smith, M.L.; Sullivan, G.M.; Tahir, S.K.; Tse, C.; Wendt, M.D.; Xiao, Y.; Xue, J.C.; Zhang, H.; Humerickhouse, R.A.; Rosenberg, S.H.; Elmore, S.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med., 2013, 19(2), 202-208.
[http://dx.doi.org/10.1038/nm.3048] [PMID: 23291630]
[26]
Gandhi, L.; Camidge, D.R.; Ribeiro de Oliveira, M.; Bonomi, P.; Gandara, D.; Khaira, D.; Hann, C.L.; McKeegan, E.M.; Litvinovich, E.; Hemken, P.M.; Dive, C.; Enschede, S.H.; Nolan, C.; Chiu, Y.L.; Busman, T.; Xiong, H.; Krivoshik, A.P.; Humerickhouse, R.; Shapiro, G.I.; Rudin, C.M. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol., 2011, 29(7), 909-916.
[http://dx.doi.org/10.1200/JCO.2010.31.6208] [PMID: 21282543]
[27]
Rudin, C.M.; Hann, C.L.; Garon, E.B.; Ribeiro de Oliveira, M.; Bonomi, P.D.; Camidge, D.R.; Chu, Q.; Giaccone, G.; Khaira, D.; Ramalingam, S.S.; Ranson, M.R.; Dive, C.; McKeegan, E.M.; Chyla, B.J.; Dowell, B.L.; Chakravartty, A.; Nolan, C.E.; Rudersdorf, N.; Busman, T.A.; Mabry, M.H.; Krivoshik, A.P.; Humerickhouse, R.A.; Shapiro, G.I.; Gandhi, L. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res., 2012, 18, 3163-3169.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-3090] [PMID: 22496272]
[28]
Zhou, H.; Chen, J.; Meagher, J.L.; Yang, C.Y.; Aguilar, A.; Liu, L.; Bai, L.; Cong, X.; Cai, Q.; Fang, X.; Stuckey, J.A.; Wang, S. Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. J. Med. Chem., 2012, 55(10), 4664-4682.
[http://dx.doi.org/10.1021/jm300178u] [PMID: 22448988]
[29]
Zhou, H.; Aguilar, A.; Chen, J.; Bai, L.; Liu, L.; Meagher, J.L.; Yang, C.Y.; McEachern, D.; Cong, X.; Stuckey, J.A.; Wang, S. Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity. J. Med. Chem., 2012, 55(13), 6149-6161.
[http://dx.doi.org/10.1021/jm300608w] [PMID: 22747598]
[30]
Chen, J.; Zhou, H.; Aguilar, A.; Liu, L.; Bai, L.; McEachern, D.; Yang, C.Y.; Meagher, J.L.; Stuckey, J.A.; Wang, S. Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J. Med. Chem., 2012, 55(19), 8502-8514.
[http://dx.doi.org/10.1021/jm3010306] [PMID: 23030453]
[31]
Aguilar, A.; Zhou, H.; Chen, J.; Liu, L.; Bai, L.; McEachern, D.; Yang, C.Y.; Meagher, J.; Stuckey, J.; Wang, S. A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J. Med. Chem., 2013, 56(7), 3048-3067.
[http://dx.doi.org/10.1021/jm4001105] [PMID: 23448298]
[32]
Bai, L.; Chen, J.; McEachern, D.; Liu, L.; Zhou, H.; Aguilar, A.; Wang, S. BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS One, 2014, 9(6) e99404
[http://dx.doi.org/10.1371/journal.pone.0099404] [PMID: 24901320]
[33]
Friberg, A.; Vigil, D.; Zhao, B.; Daniels, R.N.; Burke, J.P.; Garcia-Barrantes, P.M.; Camper, D.; Chauder, B.A.; Lee, T.; Olejniczak, E.T.; Fesik, S.W. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J. Med. Chem., 2013, 56(1), 15-30.
[http://dx.doi.org/10.1021/jm301448p] [PMID: 23244564]
[34]
Song, L.; Coppola, D.; Livingston, S.; Cress, D.; Haura, E.B. Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol. Ther., 2005, 4(3), 267-276.
[http://dx.doi.org/10.4161/cbt.4.3.1496] [PMID: 15753661]
[35]
Ding, Q.; He, X.; Xia, W.; Hsu, J.M.; Chen, C.T.; Li, L.Y.; Lee, D.F.; Yang, J.Y.; Xie, X.; Liu, J.C.; Hung, M.C. Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res., 2007, 67(10), 4564-4571.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1788] [PMID: 17495324]
[36]
Miyamoto, Y.; Hosotani, R.; Wada, M.; Lee, J.U.; Koshiba, T.; Fujimoto, K.; Tsuji, S.; Nakajima, S.; Doi, R.; Kato, M.; Shimada, Y.; Imamura, M. Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology, 1999, 56(1), 73-82.
[http://dx.doi.org/10.1159/000011933] [PMID: 9885381]
[37]
Brotin, E.; Meryet-Figuière, M.; Simonin, K.; Duval, R.E.; Villedieu, M.; Leroy-Dudal, J.; Saison-Behmoaras, E.; Gauduchon, P.; Denoyelle, C.; Poulain, L. Bcl-XL and MCL-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis. Int. J. Cancer, 2010, 126(4), 885-895.
[PMID: 19634140]
[38]
Simonin, K.; Brotin, E.; Dufort, S.; Dutoit, S.; Goux, D.; N’diaye, M.; Denoyelle, C.; Gauduchon, P.; Poulain, L. Mcl-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin-resistant ovarian carcinoma cells. Mol. Cancer Ther., 2009, 8(11), 3162-3170.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0493] [PMID: 19887550]
[39]
Derenne, S.; Monia, B.; Dean, N.M.; Taylor, J.K.; Rapp, M.J.; Harousseau, J.L.; Bataille, R.; Amiot, M. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood, 2002, 100(1), 194-199.
[http://dx.doi.org/10.1182/blood.V100.1.194] [PMID: 12070027]
[40]
Andersen, M.H.; Becker, J.C.; Thor Straten, P. The antiapoptotic member of the Bcl-2 family Mcl-1 is a CTL target in cancer patients. Leukemia, 2005, 19(3), 484-485.
[http://dx.doi.org/10.1038/sj.leu.2403621] [PMID: 15618955]
[41]
Burke, J.P.; Bian, Z.; Shaw, S.; Zhao, B.; Goodwin, C.M.; Belmar, J.; Browning, C.F.; Vigil, D.; Friberg, A.; Camper, D.V.; Rossanese, O.W.; Lee, T.; Olejniczak, E.T.; Fesik, S.W. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J. Med. Chem., 2015, 58(9), 3794-3805.
[http://dx.doi.org/10.1021/jm501984f] [PMID: 25844895]
[42]
Shaw, S.; Bian, Z.; Zhao, B.; Tarr, J.C.; Veerasamy, N.; Jeon, K.O.; Belmar, J.; Arnold, A.L.; Fogarty, S.A.; Perry, E.; Sensintaffar, J.L.; Camper, D.V.; Rossanese, O.W.; Lee, T.; Olejniczak, E.T.; Fesik, S.W. Optimization of potent and selective tricyclic indole diazepinone myeloid cell leukemia-1 inhibitors using structure-based design. J. Med. Chem., 2018, 61(6), 2410-2421.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01155] [PMID: 29323899]
[43]
Pelz, N.F.; Bian, Z.; Zhao, B.; Shaw, S.; Tarr, J.C.; Belmar, J.; Gregg, C.; Camper, D.V.; Goodwin, C.M.; Arnold, A.L.; Sensintaffar, J.L.; Friberg, A.; Rossanese, O.W.; Lee, T.; Olejniczak, E.T.; Fesik, S.W. Discovery of 2-indole-acylsulfonamide myeloid cell leukemia 1 (mcl-1) inhibitors using fragment-based methods. J. Med. Chem., 2016, 59(5), 2054-2066.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01660] [PMID: 26878343]
[44]
Lee, T.; Bian, Z.; Zhao, B.; Hogdal, L.J.; Sensintaffar, J.L.; Goodwin, C.M.; Belmar, J.; Shaw, S.; Tarr, J.C.; Veerasamy, N.; Matulis, S.M.; Koss, B.; Fischer, M.A.; Arnold, A.L.; Camper, D.V.; Browning, C.F.; Rossanese, O.W.; Budhraja, A.; Opferman, J.; Boise, L.H.; Savona, M.R.; Letai, A.; Olejniczak, E.T.; Fesik, S.W. Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors. FEBS Lett., 2017, 591(1), 240-251.
[http://dx.doi.org/10.1002/1873-3468.12497] [PMID: 27878989]
[45]
Tron, A.E.; Belmonte, M.A.; Adam, A.; Aquila, B.M.; Boise, L.H.; Chiarparin, E.; Cidado, J.; Embrey, K.J.; Gangl, E.; Gibbons, F.D.; Gregory, G.P.; Hargreaves, D.; Hendricks, J.A.; Johannes, J.W.; Johnstone, R.W.; Kazmirski, S.L.; Kettle, J.G.; Lamb, M.L.; Matulis, S.M.; Nooka, A.K.; Packer, M.J.; Peng, B.; Rawlins, P.B.; Robbins, D.W.; Schuller, A.G.; Su, N.; Yang, W.; Ye, Q.; Zheng, X.; Secrist, J.P.; Clark, E.A.; Wilson, D.M.; Fawell, S.E.; Hird, A.W. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun., 2018, 9(1), 5341-5354.
[http://dx.doi.org/10.1038/s41467-018-07551-w] [PMID: 30559424]

Rights & Permissions Print Cite
Article Metrics
53
2
© 2024 Bentham Science Publishers | Privacy Policy