CDK2 degrader Cpd 1 is a potent, selective heterobifunctional CDK2 degrader with DC50 of <10 nM and Dmax>90% in TOV21G cells, 1,000-fold selectivity versus CDK1.
Cpd 1 shows >150-fold selectivity for CDK2-cyclin E1 (IC50=1.7 nM) compared to CDK1-cyclin B1 by biochemical kinase assays
Cpd 1 significantly reduced CDK2 as well as one additional off-target protein, PIP4K2C, in approximately 8,000 proteins in PBMCs.
Cpd 1 derives enhanced CDK2 v CDK1 degradation selectivity through preferential TCF with CDK2-cyclin E1.
Cpd 1 co-degrades cyclin E1 in multiple cell types.
Cpd 1-mediated CDK2 degradation inhibitsRB-E2F pathway in CCNE1-amplified cells
Cpd 1 selectively targets CCNE1amp cancer cells and re-sensitizes palbociclib-adapted breast cells overexpressing cyclin E1.
Cpd 1 decreases cyclin E1 protein levels, in contrast to PF-07104091 which upregulates cyclin E1 protein levels, demonstrates >300-fold shift in proliferative relative IC50 from RBwt to RBKO cells.