Despite the overwhelming evidence of dysregulated RNA Polymerase I transcription in cancer, only one selective Pol I transcription inhibitor, CX5461, has entered clinical trials (Australia and Canada, haem and solid cancers). While pioneering and promising, CX-5461 is associated with additional activities (e.g., Top2a inhibition), which possibly contribute to its efficacy, toxicity profiles and acquired resistance mechanisms.
To address the need for new, improved Pol I inhibitors we have developed a series of orally available 2nd generation selective inhibitors with improved toxicology, tissue distribution (penetration of the blood brain barrier), lower plasma protein binding and higher efficacy compared to CX-5461. Preliminary studies on our new lead compound, PMR-116, has demonstrated improved survival administrated at a maximal tolerated dose (MTD:≥300 mg/kg) in murine models of acute myeloid leukemia and B-cell lymphoma. PMR116 is a selective inhibitor of Pol I transcription, with ~200x more selectivity for Pol I vs Pol II. It has a spectrum of activity on viability across a panel of cancer (GI50 ~280nM) and normal (~5μM) cell lines, which was not due to variable rDNA transcription inhibition, thus indicates a clear therapeutic window. Preliminary studies demonstrate that PMR116 impairs Pol I recruitment to the rDNA repeat in a similar fashion to CX-5461. Most importantly, however, under equivalent IC50 doses PMR-116 does not activate the DNA damage response pathway observed for CX-5461. The detailed study of this and other 2nd generation inhibitors will further expand our knowledge on the mechanism of Pol I dysregulation and drive the clinical potential of this entire drug class.