Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.
A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.
Wang
Guoping
G
Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, Michigan 48109, USA.
Nikolovska-Coleska
Zaneta
Z
Yang
Chao-Yie
CY
Wang
Renxiao
R
Tang
Guozhi
G
Guo
Jie
J
Shangary
Sanjeev
S
Qiu
Su
S
Gao
Wei
W
Yang
Dajun
D
Meagher
Jennifer
J
Stuckey
Jeanne
J
Krajewski
Krzysztof
K
Jiang
Sheng
S
Roller
Peter P
PP
Abaan
Hatice Ozel
HO
Tomita
York
Y
Wang
Shaomeng
S
D017209:Apoptosis; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006072:Gossypol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology
D001549:Benzamides; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C515128:TW-37 compound; D006072:Gossypol