Small molecule inhibitors of oncogenic miR-21

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Project Summary: Company development - Ithax Pharmaceuticals is a new spin-off biotechnology company located in Seattle and focused on developing small drug-like molecules that target non-coding RNAs in cancer and other chronic diseases. The experience of its founders’ spans drug design, RNA structure, cancer biology and biotech management, and includes the successful spin offs of several biotech companies. It gives the company an unmatched experience in the technological and commercial development of new companies in the RNA- oncology space. This Phase I STTR proposal lays out a series of experiments, beyond the scope of academic discovery, critical to advance and de-risk the commercialization plans of Ithax in the eyes of investors and pharmaceutical partners. Completion of this project will help the company fill gaps left in the academic discoveries of the founders by providing the data required to initiate medicinal chemistry optimization under a subsequent already planned phase II SBIR, and to successfully raise private capital needed for pre-clinical and clinical development. Technology - The proto-oncogenic non-coding RNA miR-21 is over-expressed in nearly every human tumor. Its over-expression is linked to unfavorable patient prognosis in multiple cancers and resistance to chemotherapeutic and immunotherapeutic treatment. Accumulating evidence in many cellular and multiple small animal models of cancers demonstrates that pharmacological inhibition of miR-21 would stop the progression of even late stage cancers, which are ‘addicted’ to this oncomiR, reduce chemo-resistance and potentiate checkpoint immunotherapy. Ithax’s first lead small molecule emerges from a collaboration between the University of Washington and the MD Anderson Cancer Center to identify new inhibitors of miRNA biogenesis. Preliminary data demonstrate that ITX-0052, a ‘Lipinski’ drug-like molecule with very safe in vitro pharmacological profile, inhibits miR-21 accumulation and reduces proliferation of gastric and pancreatic cancer cells with low M IC50 by binding directly to pre-miR-21. This project will establish the structural, biochemical and cellular mechanism of inhibition; and evaluate safety of administration, pharmacokinetics, pharmacodynamics and efficacy in murine models of gastric cancer.