Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development

  • J Med Chem. 2013 Jul 25;56(14):5979-83. doi: 10.1021/jm400487c.
Qingjie Ding  1 ,  Zhuming Zhang ,  Jin-Jun Liu ,  Nan Jiang ,  Jing Zhang ,  Tina M Ross ,  Xin-Jie Chu ,  David Bartkovitz ,  Frank Podlaski ,  Cheryl Janson ,  Christian Tovar ,  Zoran M Filipovic ,  Brian Higgins ,  Kelli Glenn ,  Kathryn Packman ,  Lyubomir T Vassilev ,  Bradford Graves
Affiliations
  • 1. Discovery Chemistry, ‡Discovery Technologies, §Discovery Oncology, ∥Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
PMID: 23808545 DOI: 10.1021/jm400487c
Abstract

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for Cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 Inhibitor, RG7388, with superior potency and selectivity.

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