Abstract Ribosome biogenesis (RiBi) is a key driver of cell growth and is strongly elevated in cancers with high MYC activity. First-generation Pol I inhibitor CX-5461 showed clinical benefits but also triggered non-specific DNA damage. PMR-116 was developed to provide selective Pol I inhibition with improved tolerability, minimal off-target induced DNA damage and stronger on-target inhibition of rRNA synthesis. PMR-116 anti-cancer activity was assessed across 100 cancer cell lines representing 20 major tumour types. It showed broad anti-proliferative activity, with GI50 values from 32-4500 nM and a median of approximately 300 nM. Normal tissue-derived cells were significantly less sensitive, with GI50 values between 6-33 μM. In vivo, PMR-116 significantly reduced tumour burden and improved survival in preclinical cancer models, including Vk*MYC multiple myeloma, CT26 colorectal cancer, MMTV-PyMT breast cancer and MLL-ENL+Nras AML (with and without TP53 mutation). Given the strong dependence of MYC-driven cancers on elevated RiBi, PMR-116 produced marked responses in MYC-addicted cancer models, consistent with exploiting a core vulnerability in MYC-amplified disease. In the large MURAL cohort of advanced prostate cancer PDX, weekly PMR-116 monotherapy at 300 mg/kg produced complete responses in two models, including a neuroendocrine prostate cancer PDX, a subtype with limited therapeutic options. A targeted 3D culture screen identified synergy between PMR-116 and PARP inhibitors, and between PMR-116 and AR-targeting agents, both of which have clear clinical translation pathways. In a phase I clinical trial, PMR-116 was well tolerated, demonstrated robust on-target activity producing approximately 50 percent reduction of rRNA synthesis in patient PBMCs within 24 hours. No global DNA damage signalling was detected at active dose levels. Overall, PMR-116 shows potent anti-cancer activity across a wide range of malignancies, with particular strength in MYC-driven tumours. Its selectivity for Pol I and favourable safety profile support its progression into an MRFF-funded phase II basket trial commencing in 2026. Citation Format: Nadine Hein, Rita Ferreira, Amee George, Katherine Hannan, Karagh Loring-White, Konstantin Panov, Eric Kusnadi, Richard Rebello, Alisee Huglo, Shelley Hedwards, Mitchell Lawrence, Mustapha Haddach, Denis Drygin, Ross D. Hannan, Luc Furic. PMR-116, a second-generation RNA polymerase I inhibitor displaying therapeutic efficacy in a broad spectrum of malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 427.
Hein et al. (Fri,) studied this question.