Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2

Cyclin-dependent kinase 2 (CDK2) plays an important role
in cell
cycle regulation and has emerged as a compelling target for the treatment
of cancer, largely because of its potential to overcome the resistance
associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors
have historically proven challenging due to undesirable safety profiles
associated with inhibiting off-target CDK isoforms. Herein, we describe
the structure-guided discovery of a series of orally bioavailable
and selective degraders of CDK2. Degrader 37 demonstrated
improved phenotypic selectivity compared to a clinical CDK2 inhibitor,
with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified
cancer cells vs nonamplified cohort. The antitumor activity of 37 in mice bearing CCNE1-amplified HCC1569 tumors correlated
with sustained >90% degradation of CDK2 and sustained 90% inhibition
of Rb phosphorylation.