Nynex Therapeutics aims to develop breakthrough therapeutics to treat cancer utilizing novel technology developed by our scientific founders, Nicholas Donato, PhD, Matt Young, PhD, Moshe Talpaz, MD and Hollis Showalter, PhD. Upregulation of proteins that confer a survival advantage is one mechanism by which cancer cells are able to evade cell death and gain resistance to treatment. Although many oncogenes have been identified, many have not been conventionally druggable.
In the last decade there has been substantial progress in understanding the specific processes and enzymes that inactivate proteins responsible for both normal and abnormal cell function. Specifically, proteins are directed toward proteolytic degradation by the proteasomal apparatus, providing a new mechanistic basis for therapeutic intervention. Proteins are targeted for proteasomal degradation through the addition of multiple ubiquitin tags. This process is counter-regulated though the action of de-ubiquitinating proteases (DUBs) that remove the appended ubiquitin tags, thus rescuing the protein from destruction. There are roughly 100 DUBs in the human genome, each with multiple specific client proteins as substrates.
Recent drug discovery activities have demonstrated that these DUBs are, in principle, druggable with conventional small molecules (Pal, Young, and Donato 2014). Blockade of a specific DUB leads to increased proteasomal degradation of its client proteins resulting in effective down-regulation or “loss of function”. This is especially interesting when considering that many DUB client proteins are not conventionally druggable in a direct fashion.
Thus, DUB inhibition may provide a first-in-class approach for many previously un-targetable proteins, including a number of oncogenes.
Dr. Nicholas Donato and his colleagues at the University of Michigan have identified the DUB USP9x (ubiquitin-specific protease 9 X-linked) as an attractive target for multiple oncologic indications. MCL-1, a known anti-apoptotic protein upregulated in multiple tumor types, is a key client protein for USP9X regulation. Through their research, novel USP9X inhibitors have been identified that can downregulate MCL-1 and other known oncogenic proteins, resulting in induction of cell death and decreased cell growth in multiple cancer cell. Over 14 million people a year are diagnosed with cancer worldwide. By developing this technology, Nynex aims to develop a novel class of anti-cancer therapeutics to help address this unmet clinical need.
2. Young M, Talpaz M, Peterson LF, Sun H, Sun D, Showalter HD, Potu H, Malek SN, Liu Y, Kandarpa M, Jakubowiak A, Ermann M, Donato NJ, Courtney SM. Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood Journal 2015
3. Potu H, Peterson LF, Kandarpa M, Pal A, Sun H, Durham A, Harms PW, Hollenhorst PC, Eskiocak U, Talpaz M, Donato NJ. Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma. Nat Commun. 2017 Feb 15.