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 (K_i = 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.

中文翻译：

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MDM2-p53 相互作用的强效小分子抑制剂 (MI-888) 在小鼠中实现完全且持久的肿瘤消退

我们之前报道了发现一类螺吲哚作为 MDM2-p53 相互作用的有效和选择性小分子抑制剂（MDM2 抑制剂）。我们在此报告了我们为改善其药代动力学特性和体内抗肿瘤活性所做的努力。我们的努力导致9 (MI-888)被鉴定为有效的 MDM2 抑制剂 ( K _i = 0.44 nM)，具有优异的药代动力学特征和增强的体内功效。化合物9能够通过口服在两种类型的人类癌症异种移植模型中实现快速、完全和持久的肿瘤消退，是迄今为止报道的最有效的 MDM2 抑制剂。