Abstract 3326: PMR-116, a second generation RNA Polymerase I inhibitor

Abstract Introduction: Inhibition of RNA Polymerase I, the enzyme responsible for the synthesis of ribosomal RNAs, the nucleic scaffold of ribosomes, has been proven as a novel therapeutic target as most cancer cells are "addicted" to ribosome biogenesis. Methods: In collaboration with Pimera Inc, we developed and tested the efficacy of a second generation RNA polymerase I inhibitor, PMR-116, in various pre-clinical cancer models. On-target activity of PMR-116 was confirmed in peripheral blood cells isolated from patients with solid tumors enrolled in a phase I trial of PMR-116. Results: PMR-116 potently inhibits Pol I transcription with ~200 fold higher selectivity towards Pol I compared to Pol II transcription. PMR-116 inhibits rRNA synthesis by stalling the Pol I complex at the rDNA promoter preventing promoter escape and consequently elongation. PMR-116 anti-cancer activity was evaluated against a panel of over 100 cancer cell lines representative of 20 major types of solid and haematological malignancies. This new Pol I inhibitor exhibited broad anti-proliferative and cytotoxic activity with an IC50 ranging from 32-4500nM and a median IC50 of 300nM. In contrast, cells derived from normal tissues were significantly less sensitive (IC50 ranging from 6-33μM). In vivo, PMR-116 significantly improved survival and reduce tumor burden in several preclinical models such as Vk*MYC transgenic model of indolent multiple myeloma, CT26 xenograft model of colorectal cancer, MMTV-PyMT transgenic model of metastatic breast cancer, mixed-lineage leukemia (MLL) -eleven nineteen leukemia (ENL) +Nras acute myeloid leukemia (+/-p53 mutation) and patient-derived xenografts of prostate cancer and AML. In a phase I trial of PMR-116, on-target activity of PMR-116 was observed in cells derived from the peripheral blood. Conclusion: PMR-116 significantly reduced cancer growth in a wide range of tumor models, including GEMM, syngeneic and PDX models. PMR-116 is undergoing clinical testing in phase I in solid tumors with the objective to determine maximum tolerated dose and identify a phase II dose. Citation Format: Luc Furic, Nadine Hein, Rita Ferreira, Konstantin Panov, Alisee Huglo, Richard Rebello, Eric Kusnadi, Denis Drygin, Mustapha Haddach, Ross Hannan. PMR-116, a second generation RNA Polymerase I inhibitor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3326.