title: Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression.
abstract: Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K(i) < 1 nM and has low nanomolar IC(50) values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.
authors.affiliation: Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Chen
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.forename: Angelo
authors.initials: A
authors.lastname: Aguilar
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Longchuan
authors.initials: L
authors.lastname: Bai
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Meagher
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C577120:BM-957; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; D051020:bcl-X Protein