AZD5438

AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2-1.7 μM), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. AZD5438 blocks cell cycling at G2-M, S and G1 phases; reduces the proportion of actively cycling cells in vivo. The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.