Abstract 2157: SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities

Abstract

Abstract Protein arginine methyltransferase 5 (PRMT5) is observed dysregulation in both solid and hematological tumors. Increasing evidences demonstrated that PRMT5 is a potential therapeutic target. Given the essential role in maintenance of adult hematopoietic cells, inhibition of PRMT5 leads to hematological toxicity. Anemia is the most common treatment related adverse event observed by PRMT5 inhibitor, such as GSK3326595, which limited the dose escalation. Therefore, developing a PRMT5 inhibitor with tumor-biased distribution could be an effective approach to avoid these target related toxicities. In this study, a novel and high selective PRMT5 inhibitor, SCR-6277 was identified. SCR-6277 inhibited the PRMT5 enzyme with an IC50 of 1.5 nM, and showed a high selectivity against other five methyltransferase isoforms (selectivity folds >1000). SCR-6277 potently inhibited the PRMT5-mediated SDMA production in Z-138 cells (IC50, 0.6 nM) and the cell proliferation (IC50, 3 nM). SCR-6277 also demonstrated robustly anti-proliferation activities on multiple PRMT5 proficient solid tumor cell lines (IC50 values ranging from 20 - 130 nM) and no inhibitory effects on PRMT5 deficient cell lines. SCR-6277 had good oral bioavailability and favorable pharmacokinetic properties. In Z-138 and 5637 xenograft models, SCR-6277 robustly inhibited tumor growth. In contrast to GSK3326595, SCR-6277 showed tumor biased distribution. Exposure of SCR-6277 in tumors were 50 folds higher than that in plasma. The extremely high T/P ratio made SCR-6277 achieve the better anti-tumor activities at lower blood exposure (Table 1). In conclusion, SCR-6277 is a novel, potent and high selective PRMT5 inhibitor. And higher tumor/plasma distribution ratio predicts SCR-6277 is a more tolerant and effective PRMT5 inhibitor in human. Table 1. Distribution and anti-tumor activity of SCR-6277 Dose TGI Plasma Conc. (ng/mL) * Tumor Conc. (ng/g) * T/P ratio GSK3326595 50 mpk,BID 87% 45 106 2 SCR-6277 15 mpk,BID 117% 20 668 50 Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Liting Xue, Wenqing Yang, Ping Chen, Renhong Tang. SCR-6277, a potent and high selective arginine methyltransferase 5 (PRMT5) inhibitor with high tumor/plasma distribution ratio demonstrated robust anti-tumor activities and decreased hematological toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2157.