Abstract 6828: Therapeutic potential of novel polyisoprenylated phosphonyl ester inhibitors in triple-negative breast cancer

Abstract Hyperactive monomeric G-proteins such as RAS are dominant “drivers” in cancer. In triple negative breast cancer (TNBC), RAS hyperactivity is due to low levels of the RAS-GTPase activating protein, RASA1, a tumor suppressor. KRAS is polyisoprenylated and methylated to become functional. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers and its specific inhibition causes cancer cell death. Polyisoprenylated phosphonyl ester inhibitors of PMPMEase (PPEIs) were designed to suppress hyperactive RAS-promoted cancers through PMPMEase inhibition. Here, we evaluated the anti-proliferative properties of the PPEIs against two TNBC cell lines, MDA-MB-468 and MDA-MB-231. The PPEIs, NSL-AB-01, NSL-AB-02 and NSL-AB-03 inhibited TNBC cells with EC50 values of 3.3 µM, 4.0 µM and 3.6 µM for MDA-MB-468 and 4.1 µM, 5.6 µM and 5.6 µM for MDA-MB-231, respectively. Following 48 h exposure to 1 µM NSL-AB-01, the proliferation of MDA-MB-231 and MDA-MB-468 cells was inhibited by 48% and 8%, respectively. At 2 to 3 µM concentrations, the proliferation of both cell lines was completely blocked. In addition, NSL-AB-01 inhibited the migration of MDA-MB-231 and MDA-MB-468 cells by 95% at 5 µM and 73% at 3 µM, respectively, thereby suggesting potential antimetastatic effects of the PPEIs. Further investigations are in progress to ascertain the molecular mechanisms underlying these effects. Overall, these findings suggest the therapeutic potential of PPEIs as novel agents for TNBC and other cancers with activated G-protein signaling. Citation Format: Joshua K. Ablordeppey, Amarender Burra, Kweku Ofosu-Asante, Jahnissi Odoom, Nazarius S. Lamango. Therapeutic potential of novel polyisoprenylated phosphonyl ester inhibitors in triple-negative breast cancer [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 6828.