A Possibility of Synthetic Lethality: Wee1 Kinase as a Promising Treating Target for Cancer

Wee kinases, including Wee1, Myt1 (PKMYT1) and Wee2, serve as critical regulators of the DNA damage response by inhibiting the G2/M transition and have attracted increasing attention as a targetable vulnerability in TP53-deficient cancers. Wee1 is the fastest progressing member in clinical research, and its inhibitors such as AZD-1775 and ZN-c3 are under clinical evaluation. Because toxicity and resistance persist with existing agents, research is moving toward newer strategies such as protein degradation technologies. Proceeding from sequence and structure, we, for the first time, use chemoinformatics to delineate the chemical space of the Wee1 binding pocket and classify reported inhibitors into three pocket engagement types, thereby constructing a high-resolution pocket map and an anchorable Markush for designing inhibitors with high selectivity and activity. We further summarize design principles for targeted degradation of Wee1 and outline combination strategies grounded in synthetic lethality, and we curate recent preclinical and ongoing clinical advances with discussion of biomarker-guided enrollment and dosing schedules. By linking structural mechanisms to pharmacology and clinical placement, this review provides an actionable framework for next-generation Wee1-directed drug design and translation in oncology.