2. Academic Validation
  3. Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

  • ACS Med Chem Lett. 2013 Apr 2;4(5):466-9. doi: 10.1021/ml4000657.
Binh Vu 1,  Peter Wovkulich 1,  Giacomo Pizzolato 1,  Allen Lovey 1,  Qingjie Ding 1,  Nan Jiang 1,  Jin-Jun Liu 1,  Chunlin Zhao 1,  Kelli Glenn 1,  Yang Wen 1,  Christian Tovar 1,  Kathryn Packman 1,  Lyubomir Vassilev 1,  Bradford Graves 1
Affiliations

Affiliation

  • 1 Discovery Chemistry, Discovery Oncology, Discovery Technologies, Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
PMID: 24900694 DOI: 10.1021/ml4000657
Abstract

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the Proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to Cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 Inhibitor designed to occupy the p53-binding pocket of MDM2. In Cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, Apoptosis, and inhibition or regression of human tumor xenografts.

Keywords

MDM2; RG7112; cancer; p53; protein−protein interaction.

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