WEE1 G2 checkpoint kinase (WEE1) (WEE1)

WEE1 G2 checkpoint kinase is a nuclear serine/threonine-protein kinase that serves as a critical regulator of the cell cycle, specifically governing the transition from the G2 phase to mitosis [1, 2]. It functions by phosphorylating and inactivating cyclin-dependent kinase 1 (CDK1) at the tyrosine 15 residue, thereby preventing premature entry into mitosis and allowing time for the repair of damaged DNA [2, 6, 10]. In many cancers, particularly those with TP53 mutations that disable the G1 checkpoint, tumor cells become excessively dependent on the WEE1-mediated G2/M checkpoint to maintain genomic integrity [1, 7, 11]. Therapeutic inhibition of WEE1, using small molecules like adavosertib (AZD1775), exploits this vulnerability by forcing cancer cells with unrepaired DNA damage into mitosis, leading to mitotic catastrophe and apoptosis [1, 7, 16]. This approach, often referred to as synthetic lethality, is currently being investigated in clinical trials both as a monotherapy and in combination with DNA-damaging chemotherapies or other targeted agents [8, 9, 17]. Beyond its role at the G2/M transition, WEE1 also regulates the S phase by modulating CDK2 activity, which is essential for proper DNA replication [10, 16]. Clinical development of WEE1 inhibitors has highlighted significant antitumor activity in ovarian, endometrial, and breast cancers, particularly in patients selected via molecular biomarkers [4, 8, 13]. However, therapeutic use is often limited by toxicities such as myelosuppression and gastrointestinal distress, necessitating careful dosing schedules [1, 13, 17].

Other names

WEE1huWee1-like protein kinaseWEE1AMitosis inhibitor protein kinase wee1

WEE1 inhibition, G2/M checkpoint abrogation