Structure-based design of potent non-peptide MDM2 inhibitors
Structure-based design of potent non-peptide MDM2 inhibitors
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DOI：
10.1021/ja051147z
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发表时间：
2005-07-27
影响因子：
15
通讯作者：
Wang, SM
中科院分区：
文献类型：
--
作者：
Ding, K;Lu, Y;Wang, SM
报道了一类以p53、−、mdm2蛋白、−蛋白相互作用为靶点的非肽小分子mdm2抑制剂的结构设计。最有效的化合物1dd与mdm2蛋白结合，Ki值为86 nM，是天然P53肽(残基16−27)的18倍。化合物1对野生型P53对LNCaP前列腺癌LNCaP细胞生长的抑制作用较强，而对P53缺失的PC-3前列腺癌细胞仅表现出较弱的活性。重要的是，1D对正常前列腺上皮细胞的毒性最小。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以设计高效、非肽、细胞渗透、小分子的抑制剂来靶向蛋白质−蛋白质相互作用，这在化学生物学和药物设计中仍然是一个非常具有挑战性的领域。
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 compound1dbinds to MDM2 protein with aKivalue of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16−27). Compound1dis 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,1dhas 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.