Wee1/Myt1 inhibitor SGR-3515

An orally bioavailable inhibitor of Wee1-like protein kinase (Wee1; Wee1A kinase; WEE1hu) and membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1; Myt1), with potential antineoplastic activity. Upon oral administration, Wee1/Myt1 inhibitor SGR-3515 targets, binds to and inhibits the activity of Wee1 and Myt1. This inhibits cyclin-dependent kinase 1 (CDK1; CDC2) and 2 (CDK2) phosphorylation, promotes both premature mitosis and a prolonged mitotic arrest, and leads to the accumulation of unrepaired DNA damage and apoptosis in susceptible tumor cells, such as CCNE1-overexpressing tumor cells. 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. Myt1 phosphorylates CDK1 specifically when CDK1 is complexed to cyclins, which blocks progression from G2 into mitosis. Upregulation of Myt1 may play a role in the acquired resistance to Wee1 inhibitors, as both kinases phosphorylate and inhibit CDK1/cyclin B complexes.