Discovery (Lead Identification)
The proto-oncogene c-Myc is deregulated and overexpressed in ~70% of all cancers. Thus, c-Myc is an attractive therapeutic target since disrupting c-Myc activity could be used as pan-chemotherapy. Beyond cancer, Myc is also a positive effector of tissue inflammation, and its function has been implicated in the pathophysiology of heart failure. Because c-Myc is a transcription factor, a rationally designed small molecule targeting c-Myc would be required to exhibit significant specificity. Unfortunatly, several physical characteristics of Myc make it a very difficult protein to target and, to date, there are no approved drugs targeting c-Myc.
The invention is directed to small molecules that stabilize the transcription repressing quadruplex in the c-Myc gene promoter region. Invention compounds target c-Myc at the transcriptional level are shown to inhibit c-Myc expression. Invention compounds are effective in selective killing in a variety of c-Myc driven cancer cell lines, including leukemia, non-small-cell lung cancer, colon, central nervous system, melanoma, ovarian, renal prostate and breast. Minimal unwanted activity is observed in peripheral blood mononucleocytes or cancer cell lines that resist inhibition of c-Myc protein expression.
Current efforts are focused on developing more potent molecules with improved ability to decrease c-Myc expression and superior bioavailability. Through synthesis of a focused library of analogs, we have identified inhibitors with improved Kd values for the quadruplex, improved toxicity towards c-Myc-driven cancer cells, and improved efficacy for decreasing c-Myc expression. By solving an NMR structure of the quadruplex in complex with the small molecule, we have begun to establish a molecular basis for selectivity observed in cell-based and biophysical assays and are working to use this information to design improved inhibitors. Additionally, we show that one compound of interest is orally bioavailable, albeit with a Cmax in oral dosing slightly below the concentration required for oral efficacy.
This technology is available for licensing and co-development to qualified entities.