CDK2 degrader NKT3964

An orally bioavailable, targeted degrader composed of an E3 ubiquitin ligase-binding moiety that is conjugated, via a linker, to a cyclin-dependent kinase 2 (CDK2)-binding moiety using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. Upon oral administration of CDK2 degrader NKT3964, the CDK2-binding moiety specifically targets and binds to CDK2 on tumor cells while the E3 ubiquitin ligase-binding moiety targets and binds to E3 ubiquitin ligase, thereby creating a ternary complex. This induces E3 ligase ubiquitination and proteasome-mediated degradation of CDK2, and inhibits the activity of CDK2. This inhibits retinoblastoma (Rb) phosphorylation and blocks G1/S transition, which leads to cell cycle arrest, the induction of apoptosis, and the inhibition of tumor cell proliferation. CDK2, in complex with cyclin E1 (CCNE1; CCNE-1), phosphorylates Rb, which leads to E2F target gene expression and G1 to S-phase cell cycle progression. CDK2 and CCNE1 are overexpressed in various tumor cell types. NKT3964 does not cause cyclin E accumulation.