Abstract 4229: GTA182: A potentially best-in-class, MTA-cooperative PRMT5 inhibitor for MTAP-deleted advanced solid tumors

Background: GTA182 is a second-generation, MTA-cooperative PRMT5 inhibitor developed to selectively target MTAP-null tumors, where MTAP deletion (often co-occurring with CDKN2A loss) creates a synthetic lethal vulnerability. Unlike first-generation inhibitors, GTA182 is optimized for high selectivity in MTAP-deleted versus MTAP wild-type cells, dose-proportional exposure, and CNS penetration, positioning it as a potential best-in-class treatment. GTA182 is currently in phase 1 clinical trials for advanced solid tumors with homozygous MTAP deletion. Methods: Using structure-based design and advanced molecular modeling, GTA182 was optimized for enhanced ADME-PK properties, achieving broad systemic and CNS exposure. Preclinical selectivity and anti-tumor efficacy were evaluated in both MTAPwt and MTAP-null tumor models, with comparisons made against existing second-generation PRMT5 inhibitors. Results: GTA182 demonstrated over 100-fold selectivity for MTAP-null cells, with strong anti-tumor efficacy at 3 mg/kg, substantially outperforming competitor compounds. Additionally, GTA182’s optimized dose-proportional exposure profile resulted in a 30-fold multiple of exposure, with a therapeutic index up to 23-fold in murine mouse models, supporting its favorable safety margin and once-daily dosing. Effective blood-brain barrier penetration, exemplified by high Kp,uu and robust activity in the orthotopic U87 glioblastoma model, further supports its potential to treat CNS malignancies. Preliminary combination data with PD-1 inhibitors in MTAP-null osteosarcoma models suggest promising synergy, reinforcing GTA182’s versatility and potential best-in-class status. Conclusion: GTA182 represents a highly selective, MTA-cooperative PRMT5 inhibitor with significant preclinical efficacy and a broad therapeutic window. GTA182 is now advancing through phase 1 trials with the aim to establish safety, pharmacokinetics, and efficacy in MTAP-deleted advanced tumors. With the potential to safely address both CNS and non-CNS malignancies, GTA182 is positioned to emerge as a differentiated therapeutic in precision oncology. Citation Format: Weifeng Mao, Bing Yao, Yanfeng Zhou, Wei Liu, Xiangping Zhang, Minghua Wang, Yingqi Hua, Wei Sun, Haoran Mu, Yining Tao, Qi Zhang, Mai Le, Corrine Zeng, Xiao-Hui Gu, Mingxi Li, James Joseph, Fred Aswad. GTA182: A potentially best-in-class, MTA-cooperative PRMT5 inhibitor for MTAP-deleted advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4229.