title: Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity.
abstract: Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
authors: Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-0934, USA.
authors: Haibin
authors: H
authors: Zhou
authors: Angelo
authors: A
authors: Aguilar
authors: Jianfang
authors: J
authors: Chen
authors: Longchuan
authors: L
authors: Bai
authors: Liu
authors: L
authors: Liu
authors: Jennifer L
authors: JL
authors: Meagher
authors: Chao-Yie
authors: CY
authors: Yang
authors: Donna
authors: D
authors: McEachern
authors: Xin
authors: X
authors: Cong
authors: Jeanne A
authors: JA
authors: Stuckey
authors: Shaomeng
authors: S
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C575265:5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)-butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid; C575264:5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-ethyl-2-methyl-1H-pyrrole-3-carboxylic acid; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D051020:bcl-X Protein