Download MendeleyDiscovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
Furet, P., Masuya, K., Kallen, J., Stachyra-Valat, T., Ruetz, S., Guagnano, V., Holzer, P., Mah, R., Stutz, S., Vaupel, A., Chene, P., Jeay, S., Schlapbach, A.(2016) Bioorg Med Chem Lett 26: 4837-4841
- PubMed: 27542305
- DOI: https://doi.org/10.1016/j.bmcl.2016.08.010
- Primary Citation of Related Structures:
5LN2 - PubMed 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.
Organizational Affiliation:
Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland. Electronic address: [email protected].
