Ding Ke, Lu Yipin, Nikolovska-Coleska Zaneta, Wang Guoping, Qiu Su, Shangary Sanjeev, Gao Wei, Qin Dongguang, Stuckey Jeanne, Krajewski Krzysztof, Roller Peter P, Wang Shaomeng
Department of Internal Medicine, Comprehensive Cancer Center, Life Sciences Institute, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, 48109, USA.
J Med Chem. 2006 Jun 15;49(12):3432-5. doi: 10.1021/jm051122a.
Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value of 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation of p53 function and in inhibition of cell growth in cancer cells with wild-type p53 status. MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells.
成功设计出了高效、特异的MDM2-p53相互作用非肽小分子抑制剂。最有效的抑制剂（MI-63）与MDM2结合的K(i)值为3 nM，对Bcl-2/Bcl-xL蛋白的选择性超过10000倍。MI-63在激活p53功能以及抑制具有野生型p53状态的癌细胞生长方面非常有效。MI-63对p53缺失的癌细胞具有优异的特异性，对正常细胞的毒性极小。
