Abstract 6821: The anticancer effects of polyisoprenylated phosphonyl ester inhibitors (PPEIs) of PMPMEase in pancreatic cancer cells

Abstract Monomeric G-proteins such KRAS, CDC42, RHOA, and RAC1 are polyisoprenylated and methylated to become fully functional. Polyisoprenylated protein methyl transferase (PPMTase) and polyisoprenylated methylated protein methyl esterase (PMPMEase) appear to regulate G-protein function. Previous studies showed that PMPMEase inhibition causes cancer cell death. In the current study, polyisoprenylated phosphonyl ester inhibitors (PPEIs) were developed as t, t, -farnesyl-targeted irreversible PMPMEase inhibitors. Experiments were conducted with two pancreatic cancer cell lines, MIA PaCa-2 and PANC-1. NSL-AB-01, NSL-AB-02, and NSL-AB-03 suppressed pancreatic MIA PaCa-2 cells cancer cell viability with EC50 values of 4.5, 4.8, and 4.6 µM, respectively, and 5.0, 6.4, and 5.1 µM for PANC-1 cells, respectively. Proliferation was inhibited by 99% and 95% for MIA PaCa-2 and PANC-1 cells at low micromolar PPEIs concentrations, respectively. PPEIs induced caspase activity by over 150% for both cell lines. Phosphorylation of MAPK proteins ERK1/2, MEK1/2, and CRAF were reduced by 77%, 50%, and 42% for MIA PaCa-2 cells, respectively. In PANC-1 cells, ERK1/2 phosphorylation decreased by 75%, while MEK1/2 increased by 140%. The PI3K/AKT proteins, S6 Kinase, PI3K, and AKT, were activated through phosphorylation by 19, 20, and 94%, in MIA PaCa-2 cells. However, opposing effects were observed in PANC-1 cells whereby PDK1 and PI3K phosphorylation were significantly decreased by 30 and 40%, respectively. PPEIs treatment caused actin filaments to become diffused, retracted, and clustered, causing the cancer cells to lose shape and become rounded. These findings show the potential role of PPEIs in disrupting cancer cell proliferation and, consequently, cancer progression. Citation Format: Jahnissi Odoom, Amarender Burra, Kweku Ofosu-Asante, Justin Mensah-Mamfo, Joshua Ablordeppey, Nazarius Lamango. The anticancer effects of polyisoprenylated phosphonyl ester inhibitors (PPEIs) of PMPMEase in pancreatic cancer cells [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 6821.