Definition

An orally bioavailable small molecule inhibitor of the human tyrosine kinase Wee1 (Wee1-like protein kinase; Wee1A kinase; WEE1hu), with potential antineoplastic activity. Upon oral administration, Wee1 inhibitor APR-1051 targets, binds to and inhibits the activity of Wee1. Inhibition of Wee1 inhibits cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) phosphorylation, promotes both premature mitosis and a prolonged mitotic arrest, which results in the accumulation of unrepaired DNA damage. This leads to apoptosis in susceptible tumor cells, such as p53-deficient or mutated human cancers that lack the G1 checkpoint, and G1/S-specific cyclin-E1 (CCNE1)-overexpressing tumor cells that coordinate with CDK2 to facilitate G1/S progression of cell cycle. Overexpression of Wee1 occurs in several cancer types and high expression of Wee1 is associated with poor outcomes. Wee1 phosphorylates CDK1 and CDK2, which blocks cell cycle progression from S/G2 to M phase, and G1 to S phase; it negatively regulates the G2 checkpoint by disallowing entry into mitosis in response to DNA damage.