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