Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
Basic Information
ID: ALA4431357
Journal: Bioorg Med Chem Lett
Title: Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
Authors: Furet P, Masuya K, Kallen J, Stachyra-Valat T, Ruetz S, Guagnano V, Holzer P, Mah R, Stutz S, Vaupel A, Chène P, Jeay S, Schlapbach A.
Abstract: The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.
CiteXplore: 27542305
DOI: 10.1016/j.bmcl.2016.08.010
Patent ID: ┄