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

  • J Med Chem. 2009 Dec 24;52(24):7970-3. doi: 10.1021/jm901400z.
Shanghai Yu  1 ,  Dongguang Qin ,  Sanjeev Shangary ,  Jianyong Chen ,  Guoping Wang ,  Ke Ding ,  Donna McEachern ,  Su Qiu ,  Zaneta Nikolovska-Coleska ,  Rebecca Miller ,  Sanmao Kang ,  Dajun Yang ,  Shaomeng Wang
Affiliations
  • 1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
PMID: 19928922 DOI: 10.1021/jm901400z
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.