Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold

Journal of Medicinal Chemistry

Volumn 55, Issue 10, 2012, Pages 4664-4682

  Zhou, Haibin ^a   Chen, Jianfang ^a   Meagher, Jennifer L ^b   Yang, Chao Yie ^a   Aguilar, Angelo ^a   Liu, Liu ^a   Bai, Longchuan ^a   Cong, Xin ^a   Cai, Qian ^a   Fang, Xueliang ^a   Stuckey, Jeanne A ^b   Wang, Shaomeng ^a  

^a Medicinal Chemistry and Pharmacology   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 CHLOROPHENYL) 1 (3,4 DIHYDROXYBUTYL) N [3 (4 METHYLPIPERAZIN 1 YL)PROPYL] 3 PHENYL 1H PYRROLE 2 CARBOXAMIDE; 4 (4 CHLOROPHENYL) 1 [2 (2,2 DIMETHYL 1,3 DIOXOLAN 4 YL)ETHYL] N [3 (4 METHYLPIPERAZIN 1 YL)PROPYL] 3 [4 [4 (4 NITROPHENYL)PIPERAZIN 1 YL]PHENYL] 1H PYRROLE 2 CARBOXAMIDE; 4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; 4 [[4 (DIMETHYLAMINO) 1 (PHENYLTHIO)BUT 2 YL]AMINO] 3 NITRO N [4 (PIPERAZIN 1 YL)PHENYL]BENZENESULFONAMIDE; 4 [[4 (DIMETHYLAMINO) 1 (PHENYLTHIO)BUT 2 YL]AMINO] 3 NITRO N PHENYLBENZENESULFONAMIDE; 4 [[4 (DIMETHYLAMINO) 1 (PHENYLTHIO)BUT 2 YL]AMINO] 3 NITROPHENYL]SULFONYL] 4 ETHYNYLBENZAMIDE; 4 [[4 (DIMETHYLAMINO) 1 (PHENYLTHIO)BUT 2 YL]AMINO] N (4 ETHYNYLPHENYL) 3 NITROBENZENESULFONAMIDE; 4 FLUORO 3 NITRO N PHENYLBENZENESULFONAMIDE; ETHYL 4 (4 CHLOROPHENYL) 1 [2 (2,2 DIMETHYL 1,3 DIOXOLAN 4 YL)ETHYL] 3 (3 IODOPHENYL) 1H PYRROLE 2 CARBOXYLATE; ETHYL 4 (4 CHLOROPHENYL) 1 [2 (2,2 DIMETHYL 1,3 DIOXOLAN 4 YL)ETHYL] 3 PHENYL 1H PYRROLE 2 CARBOXYLATE; ETHYL 4 (4 CHLOROPHENYL) 3 (3 IODOPHENYL) 1H PYRROLE 2 CARBOXYLATE; ETHYL 4 (4 CHLOROPHENYL) 3 (4 IODOPHENYL) 1H PYRROLE 2 CARBOXYLATE; ETHYL 4 (4 CHLOROPHENYL) 3 PHENYL 1H PYRROLE 2 CARBOXYLATE; H 1417; H 146; NAVITOCLAX; PROTEIN BCL 2; PROTEIN BCL 2 INHIBITOR; PROTEIN BCL XL; PROTEIN BCL XL INHIBITOR; PROTEIN INHIBITOR; SCAFFOLD PROTEIN; TERT BUTYL 4 [4 (4 FLUORO 3 NITROPHENYLSULFONAMIDO)PHENYL]PIPERAZINE 1 CARBOXYLATE; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; BINDING AFFINITY; CANCER CELL CULTURE; CELL ACTIVITY; CELL DEATH; CELL GROWTH; CHEMICAL STRUCTURE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG APPROVAL; DRUG DESIGN; FOOD AND DRUG ADMINISTRATION; HUMAN; HUMAN CELL; IC 50; LUNG SMALL CELL CANCER; PROTEIN BINDING; PROTEIN STRUCTURE; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; BCL-X PROTEIN; CELL DEATH; CELL LINE, TUMOR; CELL PROLIFERATION; CRYSTALLOGRAPHY, X-RAY; DRUG SCREENING ASSAYS, ANTITUMOR; FLUORESCENCE POLARIZATION; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PIPERAZINES; PROTEIN BINDING; PROTO-ONCOGENE PROTEINS C-BCL-2; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 84861513975     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300178u     Document Type: Article

References (38)

1. Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation Cell 2011, 144 (5) 646-674
2. Ziegler, D. S.; Kung, A. L. Therapeutic targeting of apoptosis pathways in cancer Curr. Opin. Oncol. 2008, 20 (1) 97-103 (Pubitemid 350190988)
3. Reed, J. C. Apoptosis-based therapies Nat. Rev. Drug Discovery 2002, 1 (2) 111-121 (Pubitemid 41646518)
4. Cory, S.; Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch Nat. Rev. Cancer 2002, 2 (9) 647-656 (Pubitemid 37328916)
5. Cory, S.; Adams, J. M. Killing cancer cells by flipping the Bcl-2/Bax switch Cancer Cell 2005, 8 (1) 5-6 (Pubitemid 40991809)
6. Labi, V.; Erlacher, M.; Kiessling, S.; Villunger, A. BH3-only proteins in cell death initiation, malignant disease and anticancer therapy Cell Death Differ. 2006, 13 (8) 1325-1238
7. Lessene, G.; Czabotar, P. E.; Colman, P. M. BCL-2 family antagonists for cancer therapy Nat. Rev. Drug Discovery 2008, 7 (12) 989-1000
8. Di Micco, S.; Vitale, R.; Pellecchia, M.; Rega, M. F.; Riva, R.; Basso, A.; Bifulco, G. Identification of lead compounds as antagonists of protein Bcl-xL with a diversity-oriented multidisciplinary approach J. Med. Chem. 2009, 52 (23) 7856-7867
9. Feng, Y.; Ding, X.; Chen, T.; Chen, L.; Liu, F.; Jia, X.; Luo, X.; Shen, X.; Chen, K.; Jiang, H.; Wang, H.; Liu, H.; Liu, D. Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors J. Med. Chem. 2010, 53 (9) 3465-3479
10. Wei, J.; Stebbins, J. L.; Kitada, S.; Dash, R.; Placzek, W.; Rega, M. F.; Wu, B.; Cellitti, J.; Zhai, D.; Yang, L.; Dahl, R.; Fisher, P. B.; Reed, J. C.; Pellecchia, M. BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins J. Med. Chem. 2010, 53 (10) 4166-4176
11. Wei, J.; Kitada, S.; Stebbins, J. L.; Placzek, W.; Zhai, D.; Wu, B.; Rega, M. F.; Zhang, Z.; Cellitti, J.; Yang, L.; Dahl, R.; Reed, J. C.; Pellecchia, M. Synthesis and biological evaluation of Apogossypolone derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins J. Med. Chem. 2010, 53 (22) 8000-8011
12. Rega, M. F.; Wu, B.; Wei, J.; Zhang, Z.; Cellitti, J. F.; Pellecchia, M. SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1 J. Med. Chem. 2011, 54 (17) 6000-6013
13. Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer, A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. G.; Ng, S.; Nimmer, P. M.; O'Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B.; Wendt, M. D.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours Nature 2005, 435 (7042) 677-681 (Pubitemid 40825512)
14. 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
15. Tse, C.; Shoemaker, A. R.; Adickes, J.; Anderson, M. G.; Chen, J.; Jin, S.; Johnson, E. F.; Marsh, K. C.; Mitten, M. J.; Nimmer, P.; Roberts, L.; Tahir, S. K.; Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S. H.; Elmore, S. W. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor Cancer Res. 2008, 68 (9) 3421-3428
16. Sleebs, B. E.; Czabotar, P. E.; Fairbrother, W. J.; Fairlie, W. D.; Flygare, J. A.; Huang, D. C.; Kersten, W. J.; Koehler, M. F.; Lessene, G.; Lowes, K.; Parisot, J. P.; Smith, B. J.; Smith, M. L.; Souers, A. J.; Street, I. P.; Yang, H.; Baell, J. B. Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity J. Med. Chem. 2011, 54 (6) 1914-1926
17. Muchmore, S. W.; Sattler, M.; Liang, H.; Meadows, R. P.; Harlan, J. E.; Yoon, H. S.; Nettesheim, D.; Chang, B. S.; Thompson, C. B.; Wong, S. L.; Ng, S. L.; Fesik, S. W. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death Nature 1996, 381 (6580) 335-341
18. 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 (Pubitemid 47278856)
19. 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 (Pubitemid 46332978)
20. Bullington, J. L.; Wolff, R. R.; Jackson, P. F. Regioselective preparation of 2-substituted 3,4-diaryl pyrroles: a concise total synthesis of ningalin B J. Org. Chem. 2002, 67 (26) 9439-9442 (Pubitemid 36033929)
21. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. Room-temperature palladium-catalyzed amination of aryl bromides and chlorides and extended scope of aromatic C-N bond formation with a commercial ligand J. Org. Chem. 1999, 64 (15) 5575-5580
22. Chinchilla, R.; Najera, C. The Sonogashira reaction: a booming methodology in synthetic organic chemistry Chem Rev 2007, 107 (3) 874-922 (Pubitemid 46504819)
23. Zhu, W.; Ma, D. Synthesis of aryl azides and vinyl azides via proline-promoted CuI-catalyzed coupling reactions Chem. Commun. 2004, 7, 888-889 (Pubitemid 38530286)
24. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes Angew. Chem., Int. Ed. 2002, 41 (14) 2596-2599 (Pubitemid 34803480)
25. Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted CuI-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles J. Org. Chem. 2005, 70 (13) 5164-5173 (Pubitemid 40863921)
26. Nikolovska-Coleska, Z.; Wang, R.; Fang, X.; Pan, H.; Tomita, Y.; Li, P.; Roller, P. P.; Krajewski, K.; Saito, N. G.; Stuckey, J. A.; Wang, S. Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization Anal. Biochem. 2004, 332 (2) 261-273 (Pubitemid 39485734)
27. Huang, X. Fluorescence polarization competition assay: the range of resolvable inhibitor potency is limited by the affinity of the fluorescent ligand J. Biomol. Screen. 2003, 8 (1) 34-38
28. Sybyl, a molecular modeling system, is supplied by Tripos, Inc., St. Louis, MO 63144.
29. Case, D. A.; Darden, T. A.; T., E.; Cheatham, I.; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Crowley, M.; Walker, R. C.; Zhang, W.; Merz, K. M.; B. Wang; Hayik, S.; Roitberg, A.; Seabra, G.; Kolossváry, I.; K. F. Wong; Paesani, F.; Vanicek, J.; X. Wu; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Kollman, P. A. AMBER10; University of California, San Francisco, 2008.
30. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M.; Johnson, B.; Chen, W.; Wong, M. M.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A-11; Gaussian, Inc.: Pittsburgh, PA, 2001.
31. Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water J. Chem. Phys. 1983, 79 (2) 926-935
32. Ryckaert, J.-P.; Ciccotti, G.; Berendsen, H. J. C. Numerical integration of the Cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes J. Comput. Phys. 1977, 23 (3) 327-341
33. Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald-an N.log(N) method for Ewald sums in large systems J. Chem. Phys. 1993, 98 (12) 10089-10092
34. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation mode. In Methods in Enzymology; Carter, C. W., Jr., Ed.; Academic Press: New York, 1997; Vol. 276, pp 307-326. (Pubitemid 27085611)
35. McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software J. Appl. Crystallogr. 2007, 40 (Pt 4) 658-674 (Pubitemid 47080256)
36. Bricogne, G.; Blanc, E.; Brandl, M.; Flensburg, C.; Keller, P.; Paciorek, W.; Roversi, P.; Sharff, A.; Smart, O.; Vonrhein, C.; Womack, T. BUSTER, version 2.9; Global Phasing Ltd., Cambridge, U.K., 2010.
37. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr. D: Biol. Crystallogr. 2004, 60, 2126-2132 (Pubitemid 41742764)
38. Schuttelkopf, A. W.; van Aalten, D. M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes Acta Crystallogr. D: Biol. Crystallogr. 2004, 60 (Pt 8) 1355-1363 (Pubitemid 41079731)