ZMS-4084

ZMS-4084 is a potent, selective, and orally bioavailable small molecule inhibitor of the Werner syndrome ATP-dependent helicase (WRN), currently in preclinical development by Zemisi Pharmaceutical. It specifically targets the WRN helicase domain with high affinity, inhibiting its ATPase activity and triggering the degradation of the WRN protein. This mechanism exploits the synthetic lethal relationship between WRN inhibition and microsatellite instability-high (MSI-H) status, a condition prevalent in various cancers including colorectal, endometrial, and gastric malignancies. In preclinical models, ZMS-4084 has demonstrated significant antitumor activity, including complete responses in xenograft models and efficacy in patient-derived organoids, while maintaining high selectivity over other RecQ family helicases. Its favorable pharmacokinetic profile supports its potential for oral administration in clinical settings as a tissue-agnostic therapy for MSI-H tumors.