RNA polymerase I (Pol I) is responsible for transcription of ribosomal DNA (rDNA) to produce the 47S ribosomal RNA (rRNA) precursor. Following processing of the 47S transcript, the individual 28S, 5.8S, and 18S rRNAs are produced and further assembled into mature ribosomes within the nucleolus. Increased Pol I transcriptional activity is commonly observed in many cancers, demonstrating a need for heightened ribosome biogenesis and protein synthesis. Pol I inhibition offers an attractive therapeutic opportunity but has not been thoroughly explored in the clinic. BMH-21 inhibits Pol I and causes proteasome-mediated degradation of RPA194, the large catalytic subunit of the Pol I complex. Structure-activity relationship (SAR) studies revealed key pharmacophores, but also showed that activity was limited within narrow chemical space. Further SAR efforts, summarized by this work, have produced additional scaffolds as well as addressed some off-target activity while maintaining desired RPA194 degradation potency. In addition, pharmacokinetic profiling was performed and offers a basis for further optimization. New Pol I inhibitors provide opportunities for potential cancer therapeutics.

Exploring linear and angular fused pyridoquinazolinecarboxamides as RNA polymerase I inhibitors

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.