Development of Wnt Pathway Inhibitors for Colorectal Cancer

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DESCRIPTION (provided by applicant): StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. The World Health Organization estimates that over 12 million cases of cancer were diagnosed in 2007 and that nearly 8 million cancer patients will die of their disease. Colorectal cancer represents the second most common cause of death due to cancer with 1.2 million deaths. Activating mutations in the Wnt signaling pathway are the earliest events in the genesis of colorectal cancer, and, remarkably, are present in over 90% of all cases. There is an urgent need for inhibitors of the Wnt pathway for the treatment of colorectal cancer and other Wnt-driven cancers. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. SSTI has developed a powerful biochemical screen to identify Wnt inhibitors utilizing two independent readouts of the Wnt pathway. By assessing the stability of two Wnt pathway proteins, 2-catenin and Axin, SSTI has screened and identified an FDA-approved compound (SST-024) that potently inhibits Wnt signaling (EC50~10 nM). SST-024 was previously approved for a non-cancer indication. Our studies of SST-024 indicate that it is also a potent inhibitor of colorectal cancer cell growth and viability. Importantly, SST-024 is 80 times more selective in inhibiting the growth of a colorectal cancer cell line with an activating mutation in the Wnt pathway (human SW480 cells) compared to a genetically identical cancer line that has wild-type APC restored (human SW480APC cells). Due to intellectual property issues (SST-024 is off- patent) and concerns about bioavailability, we embarked on a virtual screening approach to identify compounds with improved bioavailability and drug-like properties. One of our lead compounds from this screen, SST-163, potently inhibits Wnt signaling and blocks the growth of Wnt-driven cancer cell lines. SST-163 also selectively inhibits the growth of SW480 cells over SW480APC cells which would correlate with a therapeutic window for the treatment of cancer cells over normal tissue. We have subsequently shown in vivo efficacy using SST-163 to block the growth of human SW480 cells in a mouse xenograft model. Based on these studies, we initiated a medicinal chemistry program focused on the synthesis of SST-163 analogs that further optimized their drug-like properties. Currently, our lead optimization efforts have generated a library of more water soluble derivatives for further evaluation. As part of our initial preclinical characterization of the SST-163 class of Wnt inhibitors, we propose to test our SST-163-based library for potency against the Wnt pathway, for favorable toxicology profiles, and for bioavailability models. The most promising compounds identified in these studies will be tested for their efficacy on a series of human colorectal cancer lines that harbor activating Wnt mutations as well as mutations in other signaling pathways in order to identify the subset of patients for whom our compounds may be the most efficacious. Finally, we propose to perform studies using promising SST-163 derivatives to identify pharmacologically relevant markers for the status of Wnt signaling. Because there are no drugs on the market that target the Wnt pathway, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. In summary, SSTI has the opportunity to bring to the market the first generation of Wnt inhibitors and capture a significant share of the global market for cancer drugs. PUBLIC HEALTH RELEVANCE: Colorectal cancer is responsible for 1.2 million cases and 650,000 deaths each year. The Wnt pathway is a major growth pathway that plays a critical role in >90% of all cases and there are currently no inhibitors in the clinic. We intend to develop our lead compound Wnt pathway inhibitors through pre-clinical and clinical trials for a treatment of colorectal cancer.