Structure-Based Design of Potent Small-Molecule Inhibitors of Anti-Apoptotic Bcl-2 Proteins
Guoping Wang(Georgetown University), Zaneta Nikolovska‐Coleska(National Cancer Institute), Chao‐Yie Yang(Georgetown University), Renxiao Wang(Georgetown University Medical Center), Guozhi Tang(National Cancer Institute), Jie Guo(National Institutes of Health), Sanjeev Shangary(Georgetown University Medical Center), Su Qiu(Georgetown University Medical Center), Wei Gao(National Institutes of Health), Dajun Yang(Georgetown University), Jennifer L. Meagher(National Cancer Institute), Jeanne A. Stuckey(National Cancer Institute), Krzysztof Krajewski(National Institutes of Health), Sheng Jiang(Georgetown University Medical Center), Peter P. Roller(National Cancer Institute), Hatice Özel Abaan(Georgetown University Medical Center), York Tomita(Georgetown University), Shaomeng Wang(Georgetown University)
Cited by 294Open Access
Abstract
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.
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