AI-Empowered Discovery of the First WRN Degrader for MSI-High Cancer Therapy

The WRN helicase has recently emerged as a promising therapeutic target for microsatellite instability (MSI)-high cancers. Here, we report LXW-P1, a potent WRN degrader derived from marine bromotyrosine alkaloids. Its molecular target was identified using an AI-guided, pathway-informed perturbation transcriptomics strategy, which prioritized candidate targets from complex phenotypic responses, focusing on WRN and accelerating mechanistic discovery. Through the first total synthesis of purpuramine D, aplysamine 3, and purealidin C, coupled with systematic derivatization, we identified LXW-P1 as a synthetic intermediate with exceptional antitumor activity. Guided by AI predictions, extensive validation revealed that LXW-P1 induces proteasome-dependent WRN degradation. Mechanistic studies demonstrated that LXW-P1 directly binds to WRN, triggering its degradation and subsequently inducing DNA damage and cell cycle arrest in MSI-high cancer cells. In vivo, LXW-P1 exhibited selective inhibition of MSI tumor growth while maintaining a favorable safety profile. This work bridges marine natural product chemistry with targeted protein degradation, providing a novel therapeutic strategy for MSI-high cancers and underscoring the strategic and efficiency advantages of AI in modern drug discovery.