Discovery of GTA182, a Novel CNS-Active Tricyclic Amide MTA-Cooperative PRMT5 Inhibitor for MTAP -Deleted Cancers

Abstract Developing central nervous system (CNS) active, MTA-cooperative PRMT5 inhibitors for MTAP-deleted malignancies represents a formidable challenge. Here, we report the discovery of GTA182 via structure-based drug design. Multi-parameter optimization balanced single-digit nanomolar potency and >100-fold MTAP-deletion selectivity with dose-proportional pharmacokinetics. Optimized physicochemical properties, and minimal efflux delivered unbound brain concentrations within the efficacious range. Oral GTA182 demonstrated robust MTAP deletion-dependent efficacy, achieving net regression at 30 mg/kg (102% TGI) in MTAP-deleted HCT116 xenografts (versus 41% TGI in WT) alongside 59% regression and extended median survival (>91 days) in the orthotopic U87MG-luc glioblastoma model. In a Phase I trial (CTR20243795), GTA182 was well tolerated, shrank intracranial tumors, and achieved an overall objective response rate (ORR) approaching 30%. These properties establish GTA182 as a promising therapeutic candidate for MTAP-deleted systemic and CNS malignancies.