Abstract A089: UnAcH416 (P2), a selective PRMT1 inhibitor, disrupts tumor cell growth and stress-response pathways

Abstract Protein arginine methyltransferases (PRMTs) are critical regulators of cellular processes such as cell cycle progression, DNA repair, immune signaling, and transcriptional regulation. Among them, type I PRMTs, responsible for catalyzing asymmetric dimethylation of arginine residues, are frequently overexpressed in human cancers and represent compelling therapeutic targets. This study investigates the anticancer potential of UnAcH416 (P2), a novel peptoid-based inhibitor with selective activity against PRMT1. P2 exhibited dose-dependent antiproliferative effects across various cancer cell lines, with minimal cytotoxicity in non-malignant cells, indicating favorable tumor selectivity through cell viability and morphological analyses. Mechanistic studies demonstrated that P2 transiently inhibits PRMT1 activity and induces cell cycle arrest at the G1/S transition, as confirmed by Western blot analysis. In both MDA-MB-468 breast cancer and HCT116 colon cancer cells, P2 treatment led to elevated LC3-II levels, detected by Western blot and ELISA, suggesting the induction of autophagy as a component of its mechanism of action. Unexpectedly, P2 appeared to promote migratory behavior in cancer cells, as evidenced by accelerated wound closure in scratch assays. Additionally, combinatorial treatment with P2 and the chemotherapeutic agent paclitaxel (Taxol) resulted in reduced drug sensitivity, potentially due to altered cytoskeletal dynamics or autophagy-associated resistance mechanisms. However, gelatin zymography and MMP-9 activity assays revealed a concurrent suppression of extracellular matrix remodeling, suggesting a complex, possibly stress-related modulation of invasion pathways. Ongoing research aims to elucidate the relationship between P2-induced autophagy and epithelial-to-mesenchymal transition (EMT), as well as to explore synergy with anti-migratory agents and bioactive compounds such as doxycycline and saffron. Future studies will include in vivo validation, maximum tolerated dose (MTD) determination, hollow fiber assays, and pharmacodynamic profiling. Citation Format: Joseph Camps, Naomi Laird, Diana Soto, Corey Causey, Bryan Knuckley, Fatima K. Rehman. UnAcH416 (P2), a selective PRMT1 inhibitor, disrupts tumor cell growth and stress-response pathways [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A089.