WEE1 regulates the G2/M cell cycle checkpoint via phosphorylation of CDK1 (aka Cdc2) at Tyr15, which inhibits CDK1/cyclin B kinase activity. Inhibition of WEE1 overrides DNA damage-induced cell cycle arrest in cells with a dysfunctional G1 checkpoint and drives TP53 mutant cancer cells into mitotic catastrophe. It is therefore an attractive target for enhancing the effects of chemotherapeutic DNA-damaging therapies.