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Structure-Based Design of Potent Non-Peptide MDM2 Inhibitors

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journal contribution
posted on 2005-07-27, 00:00 authored by Ke Ding, Yipin Lu, Zaneta Nikolovska-Coleska, Su Qiu, Yousong Ding, Wei Gao, Jeanne Stuckey, Krzysztof Krajewski, Peter P. Roller, York Tomita, Damon A. Parrish, Jeffrey R. Deschamps, Shaomeng Wang
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.