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Small Molecule Anti-cancer Agents that Stabilize the MYC-G-Quadruplex

Summary
The proto-oncogene c-Myc is deregulated and overexpressed in ~70% of all cancers. Thus, c-Myc is an attractive therapeutic target. Beyond cancer, Myc is also a positive effector of tissue inflammation, and its function has been implicated in the pathophysiology of heart failure. Researchers at the National Cancer Institute (NCI) developed novel small molecules that target c-Myc at the transcriptional level, thus enabling a potential pan-cancer therapeutic. Specifically, these compounds stabilize the transcription repressing quadruplex in the c-Myc gene promoter region. The National Cancer Institute seeks parties interested in licensing or collaborative research to co-develop these therapeutic targets.'
NIH Reference Number
E-053-2015
Product Type
Keywords
  • c-Myc, G-Quadruplex (G4), Multiple Myeloma, Schneekloth
Collaboration Opportunity
This invention is available for licensing and co-development.
Contact
Description of Technology

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.

Potential Commercial Applications
  • Therapeutic for multiple myeloma, carcinoma of the cervix, colon, breast, lung and stomach 
  • Tissue Inflammation
Competitive Advantages
  • First in class drug since no c-Myc drugs have been approved for any cancer indication
  • Drug-like in nature, satisfying all of Lipinski’s rule of five parameters 
  • Orally bioavailable 
  • Decreasing c-Myc expression without affecting expression from other quadruplex-driven genes
  • Compound has significant potential for improvement with very minor structural alternations
  • The methodologies used by the lab have explored the biological potential of c-Myc G-quadruplex-stabilizing agents to a degree of complexity greater than what has ever been done before.
Inventor(s)

John S. Schneekloth (NCI), Beverley Mock (NCI), Lindsey Saunders (NCI), David Calabrese (NCI), Elena Leon (NCI), John Simmons (NCI), Kenneth Felstenstein (NCI), Peter Gareiss (Yale University)

Development Stage
Publications

Kenneth M. Felsenstein et al. [PMID 26462961]

Patent Status
  • Foreign Filed: Foreign Filed - Patent Application PCT/US2016/012222, Filed 05 Jan 2016
Therapeutic Area
Updated
Tuesday, April 3, 2018