title: Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold.
abstract: Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM.
authors.affiliation: Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, United States.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.forename: Jianfang
authors.initials: J
authors.lastname: Chen
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Meagher
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
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: Xin
authors.initials: X
authors.lastname: Cong
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.forename: Xueliang
authors.initials: X
authors.lastname: Fang
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: C574761:4-(4-chlorophenyl)-3-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)but-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid; D000970:Antineoplastic Agents; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein