基于结构的高效非肽类MDM2抑制剂设计

Structure-based design of potent non-peptide MDM2 inhibitors.

作者信息

Ding Ke, Lu Yipin, Nikolovska-Coleska Zaneta, Qiu Su, Ding Yousong, Gao Wei, Stuckey Jeanne, Krajewski Krzysztof, Roller Peter P, Tomita York, Parrish Damon A, Deschamps Jeffrey R, Wang Shaomeng

机构信息

Departments of Internal Medicine and Medicinal Chemistry and Comprehensive Cancer Center, and Life Sciences Institute, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.

出版信息

J Am Chem Soc. 2005 Jul 27;127(29):10130-1. doi: 10.1021/ja051147z.

DOI:10.1021/ja051147z

PMID:16028899

Abstract

A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to MDM2 protein with a Ki value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16-27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein-protein interaction, which remains a very challenging area in chemical biology and drug design.

摘要

报道了一类基于结构设计的非肽小分子MDM2抑制剂，其靶向p53-MDM2蛋白-蛋白相互作用。最有效的化合物1d与MDM2蛋白结合，Ki值为86 nM，比天然p53肽（第16-27位残基）的活性高18倍。化合物1d对具有野生型p53的LNCaP前列腺癌细胞的细胞生长具有强效抑制作用，而对p53缺失的PC-3前列腺癌细胞仅表现出微弱活性。重要的是，1d对正常前列腺上皮细胞的毒性极小。我们的研究提供了一个令人信服的例子，即基于结构的策略可用于设计高效、非肽、细胞可渗透的小分子抑制剂来靶向蛋白-蛋白相互作用，这在化学生物学和药物设计中仍然是一个极具挑战性的领域。