WEE1 kinase

Class

WEE1 kinase inhibitor (small molecule, ATP-competitive)

Pathway

Abrogates the G2/M DNA damage checkpoint, forcing damaged cells into mitosis (mitotic catastrophe)

WEE1 is a nuclear kinase that helps control the timing of cell division by restraining the transition from the G2 phase of the cell cycle into mitosis. It does this by inhibiting cyclin-dependent kinase 1 (CDK1), a key driver of mitotic entry, until DNA damage has been repaired. This function is called the G2/M checkpoint, and it acts as a quality-control step that prevents cells from dividing while carrying unrepaired DNA. Cancer cells frequently lose an earlier checkpoint, governed by the tumor-suppressor protein p53, making them disproportionately reliant on the G2/M checkpoint to survive DNA-damaging insults such as chemotherapy or radiation. Inhibiting WEE1 removes this remaining safeguard, forcing cells with damaged DNA to enter mitosis prematurely. The result is a lethal process termed mitotic catastrophe, in which cells attempt to divide with unresolved DNA breaks and die. This mechanism underlies interest in WEE1 inhibitors as agents that sensitize tumors to DNA-damaging therapies, particularly in cancers with p53 mutations or other defects in DNA-damage response pathways. Because the checkpoint being disabled is a general cell-cycle safeguard rather than a cancer-specific pathway, the approach is studied broadly across solid tumors with high genomic instability, typically alongside other treatments that create the DNA damage this mechanism exploits.