The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies.

Ribosome biogenesis (RiBi) is a key determinant of cell growth and proliferation and is highly elevated in cancer due to the activation by oncogenes such as MYC. First-generation RiBi inhibitor CX-5461, while demonstrating clinical potential for cancer treatment, also induces DNA damage through off-target inhibition of TOP2 and potentially other mechanisms, bringing into question RiBi as a target for cancer therapy. In this study, we test second-generation RiBi inhibitor, PMR-116. PMR-116 exhibits improved drug-like properties compared to first-generation RiBi inhibitors and has robust anti-tumour activity in the absence of global DNA damage signalling in a broad range of pre-clinical models of haematologic and solid cancers, particularly in malignancies where MYC is either the driver of disease or is elevated. Thus, our work demonstrates that RiBi is a genuine target for cancer therapy and highlights the potential to exploit a critical therapeutic vulnerability in high-MYC human cancers with dismal therapeutic outcomes. Statement of significanceDespite the development of new cancer therapies, most advanced malignancies remain incurable. We demonstrate that PMR-116, a second-generation RiBi inhibitor, has robust therapeutic efficacy in preclinical models of cancer, offering great promise to treat a broad spectrum of human solid and haematologic malignancies, especially where MYC is a driver.