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Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.

ABSTRACT: We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

SUBMITTER: Yu S

PROVIDER: S-EPMC2795799 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction.

Yu Shanghai S Qin Dongguang D Shangary Sanjeev S Chen Jianyong J Wang Guoping G Ding Ke K Ding Ke K McEachern Donna D Qiu Su S Nikolovska-Coleska Zaneta Z Miller Rebecca R Kang Sanmao S Yang Dajun D Wang Shaomeng S

Journal of medicinal chemistry 20091201 24

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model. ...[more]

PMID: 19928922

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