用于癌症治疗临床试验的小分子MDM2抑制剂
Small-molecule MDM2 inhibitors in clinical trials for cancer therapy.
作者信息
Wang Shuai, Chen Fen-Er
机构信息
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai, 200433, China.
出版信息
Eur J Med Chem. 2022 Jun 5;236:114334. doi: 10.1016/j.ejmech.2022.114334. Epub 2022 Apr 8.
Disruption of the MDM2-p53 protein-protein interaction by small-molecule inhibitors has been highly pursued by many academic laboratories and pharmaceutical companies as a promising strategy for cancer therapy. To date, based on the explanation of the cocrystal structure of MDM2 with p53, many highly potent and selective small-molecule MDM2 inhibitors have been successfully discovered and nine of them are currently under different clinical trials for cancer therapy. Herein, we will review the function of MDM2 and provide a comprehensive and updated overview of small-molecule MDM2 inhibitors in different clinical phases for cancer therapy, especially focusing on the identification and optimization, and preclinical/clinical studies of these clinical-stage MDM2 inhibitors. Challenges regarding acquired resistance and potential toxicity of MDM2 inhibitors to normal tissues and outlook are also briefly discussed, which will further guide the design of new small-molecule MDM2 inhibitors.
小分子抑制剂破坏MDM2与p53的蛋白质-蛋白质相互作用，已被许多学术实验室和制药公司高度关注，作为一种有前景的癌症治疗策略。迄今为止，基于MDM2与p53共晶体结构的解释，已成功发现了许多高效且选择性的小分子MDM2抑制剂，其中九种目前正处于针对癌症治疗的不同临床试验阶段。在此，我们将综述MDM2的功能，并全面更新概述处于不同临床阶段用于癌症治疗的小分子MDM2抑制剂，尤其着重于这些临床阶段MDM2抑制剂的鉴定与优化以及临床前/临床研究。还简要讨论了MDM2抑制剂获得性耐药以及对正常组织潜在毒性方面的挑战和前景，这将进一步指导新型小分子MDM2抑制剂的设计。
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