Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction
Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction
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DOI：
10.1021/jm051122a
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发表时间：
2006-06-15
影响因子：
7.3
通讯作者：
Wang, Shaomeng
中科院分区：
文献类型：
--
作者：
Ding, Ke;Lu, Yipin;Wang, Shaomeng
成功设计了MDM 2-p53相互作用的有效、特异性、非肽小分子抑制剂。最有效的抑制剂（MI-63）与MDM 2结合的Ki值为3 nM，并且对Bcl-2/Bcl-xL蛋白的选择性大于10000倍。MI-63在激活p53功能和抑制具有野生型p53状态的癌细胞中的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，并且对正常细胞显示出最小的毒性。
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.