Despite the overwhelming evidence of dysregulated RNA Polymerase I (Pol I) transcription of the ribosomal RNA (rRNA) genes (rDNA) in cancer, only one selective Pol I transcription inhibitor, CX-5461, has entered clinical trials. Studies using in vivo models for various blood and solid cancers have demonstrated efficacy and support a broad use for CX-5461 as a cancer therapy. A Phase I trial with patients with advanced hematological cancer reported that CX-5461 is tolerated with minimal side effects and a second trial has commenced in breast cancer.
While pioneering and promising, CX-5461 does have additional activities (e.g., Top2a inhibition and DNA damage), which possibly contributes to its efficacy, toxicity profiles and acquired resistance mechanisms.
We have developed a series of 2nd generation Pol I transcription inhibitors with improved toxicology, tissue distribution (penetrates the blood brain barrier), reduced plasma protein binding and higher efficacy compared to CX-5461. Our lead compound, PMR-116, has a high orally bioavailability, is well tolerated and improves survival in murine models of acute myeloid leukemia, B-cell lymphoma and prostate cancer.
Preliminary studies suggest PMR-116 impairs Pol I recruitment to the rDNA repeat in a similar fashion to CX-5461. Most importantly, however, under equivalent tIC50 (50% inhibition of rDNA transcription) doses PMR-116 is effective irrespective of p53 status and does not activate the DNA damage response (DRR) as observed for CX-5461. Thus, unlike CX-5461, PMR-116 may not interfere with Top2a or initiate DDR, a significant distinguishing characteristic between these two compounds. PMR-116 is poised to enter clinical trials.