Abstract 1766: PE-0260, an oral brain-penetrant MTA-cooperative PRMT5 inhibitor, drives tumor regressions in MTAP-deleted solid tumors

Abstract PE-0260 is a potent and selective oral methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor leveraging the synthetic lethal relationship of PRMT5 with methylthioadenosine phosphorylase (MTAP) gene deletion. The well-studied synthetic lethality is an attractive approach for multiple cancer treatments due to the 10-15% incidence rate of MTAP deletion in all cancers. PE-0260 shows good potency of MTAP del cell viability (<5 nM IC50) and >200X selectivity compared with isogenic MTAP WT cells. In a diverse cell line panel, PE-0260 selectively inhibits MTAP del cell lines over MTAP WT cell lines with median IC50 < 30 nM and >50X selectivity across NSCLC, GBM, pancreatic and breast cancers. This outstanding potency was successfully translated to dose-dependent anti-tumor activities observed in xenograft models with tumor regressions, and significant inhibition of symmetric dimethylarginine (SDMA) modified protein formation in tumors. Through the PK-PD analysis, on-target driven efficacy has been demonstrated, suggesting a low likelihood of off-target toxicity. PE-0260 also shows balanced in vitro ADME properties with low risk for drug-drug interactions and the capability to penetrate the blood-brain barrier. In conclusion, PE-0260 is a potential best-in-class MTA-cooperative PRMT5 inhibitor and a strong candidate for further clinical development. Citation Format: Cheng-Hao Liu, Hui-Ling Chen, Chieh-Fang Cheng, Feng-Yu Lee, Long-Zhi Lin, Hong-Ren Wang. PE-0260, an oral brain-penetrant MTA-cooperative PRMT5 inhibitor, drives tumor regressions in MTAP-deleted 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 1766.