Molecular pathways: targeting the protein kinase Wee1 in cancer

Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDKs) are a family of 14 serine/threonine protein kinases, which coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G2 into mitosis. There are two mechanisms by which the G2 checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of Wee1 kinase, which phosphorylates Cdc2. Blockade at the G2 checkpoint is especially important for p53 mutant cells because these tumors mainly rely on DNA repair at the G2 checkpoint. AZD1775 (formerly MK-1775) is a small molecule pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging anti-tumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents.  Promising combination schedules are being investigated at the moment, e.g. combining PARP-inhibition and Wee1 inhibition. Also a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the anti-tumor effect.

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