WEE-family kinases in cancer: synthetic lethal interactions and drug discovery.

The WEE-family kinases, WEE1 and PKMYT1, play critical roles in regulating the G2/M cell cycle checkpoint to maintain genomic stability. Cancer cells with DNA damage response (DDR) deficiencies become heavily reliant on WEE1 and PKMYT1 to avert mitotic catastrophe. This dependence creates a synthetic lethality vulnerability that offers a promising therapeutic strategy. While early WEE1 inhibitors faced challenges due to toxicity, next-generation highly selective agents are now advancing through clinical trials with improved safety and efficacy. Similarly, PKMYT1 inhibitors have emerged as a complementary approach, with several candidates under clinical evaluation. This review examines the evolving mechanistic basis of synthetic lethality, with emphasis on how targeted inhibition of WEE1 or PKMYT1 exploits DDR defects to selectively induce genomic instability in cancer cells. Furthermore, we highlight recent advances in selective WEE kinase inhibitors, discuss key challenges, and explore innovative strategies to accelerate their development.