A Potent Small-Molecule Inhibitor of the MDM2–p53 Interaction (MI-888) Achieved Complete and Durable Tumor Regression in Mice
Journal of Medicinal Chemistry2013Vol. 56(13), pp. 5553–5561
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Yujun Zhao, Shanghai Yu, Wei Sun, Liu Liu, Jianfeng Lü, Donna McEachern, Sanjeev Shargary, Denzil Bernard, Xiaoqin Li, Ting Zhao, Peng Zou, Duxin Sun, Shaomeng Wang
Abstract
We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
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