AZD8421 (AZD-8421) is a potent, highly selective CDK2 inhibitor with IC50 of 9 nM, >300-fold selectivity over CDK9.
AZD8421 forms hydrogen bonding interaction with Lys89 (a CDK2-specific residue) near the solvent region of the ATP-binding pocket.
AZD8421 displays high selectivity over CDK1, CDK4 and CDK6.
AZD8421 potently inhibits cell proliferation (69 nM, OVCAR3), correlated with inhibition of pRB, arrest in G1/S phase of the cell cycle and induction of senescence, in a CCNE1 amplified cell line.
AZD8421 shows combination benefit when combined with approved CDK4/6 inhibitors in CDK4/6 inhibitor resistant breast cancer cell lines.
AZD8421 potently suppresses phosphorylation of Rb, and demonstrates robust monotherapy and CDK4/6i combination activity in breast and ovarian in vivo models.
AZD8421 shows robust monotherapy activity in a CCNE1 amplified ovarian model OVCAR3 with regressions seen with monotherapy and in combination with palbociclib in CDK4/6 inhibitor resistant breast PDXs.