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J Med Chem. 2015 Aug 27;58(16):6348-58. doi: 10.1021/acs.jmedchem.5b00810. Epub 2015 Aug 5.

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

Author information

1
Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.

Abstract

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

PMID:
26181851
DOI:
10.1021/acs.jmedchem.5b00810
[Indexed for MEDLINE]

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