Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome

Targeting CDK2 with first generation CDK2 inhibitors
suffered from
a reduced therapeutic index likely due to toxicity stemming from lack
of selectivity against the CDK family and other kinases. Recently,
CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors
in the context of high levels of cyclin E expression. Discovery of
highly selective CDK2 inhibitors may minimize off-target effects,
reduce toxicity observed with first generation CDK2 inhibitors, and
allow precise targeting of aberrant cell cycle progression and resistance
mechanisms mediated by high cyclin E/CDK2 activity. To this end, we
report the discovery of AZD8421, a potent and highly selective CDK2
inhibitor, which exhibits superior selectivity for CDK2 over CDK1,
other CDK family members, and the broader human kinome. AZD8421 demonstrates
favorable pharmacokinetic properties, including excellent solubility
and robust in vitro stability. Demonstrated efficacy in an ovarian
cancer patient-derived xenograft model further supports its potential
as a therapeutic agent.