3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A−E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A−E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a Ki of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC50 in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was dec...