Gessier, Francois, Kallen, Joerg, Jacoby, Edgar, Chene, Patrick, Valat, Therese-Marie, Ruetz, Stephan, Jeay, Sebastien, Holzer, Philipp, Masuya, Keiichi and Furet, Pascal (2015) Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorganic & Medicinal Chemistry Letters, 25 (17). pp. 3621-3625. ISSN 0960894X

Abstract

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogues. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.

Item Type:	Article
Keywords:	p53, MDM2, protein-protein interaction inhibitors
Date Deposited:	18 May 2016 23:45
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26039