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, haematological 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. Thus, unlike CX- 5461, PMR-116 may not interfere with Top2a function, a significant distinguishing characteristic between these two drugs. We have also completed an investigational new drug-enabling toxicology program (in rat and dog) using the clinically-relevant route (oral) and dosing schedule (1/week), and this demonstrated that PMR-116 has a high orally bioavailability (82%) and is well tolerated. This approach of mechanistic and preclinical studies is not only critical to develop better clinical compounds, but will likely further expand our knowledge on the mechanism of Pol I dysregulation and drive the clinical potential of this entire drug class.