Development of novel WNT inhibitors to treat colorectal cancers

The National Institutes of Health National Cancer Institute awarded Stemsynergy Therapeutics Inc. $399,998 on September 3, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop novel WNT pathway inhibitors for colorectal cancer treatment.

Stemsynergy will optimize a series of small molecule WNT inhibitors, including its lead compound SSTB-178, that disrupt binding between β-catenin and BCL-9 proteins to suppress WNT signaling activity in cancer cells. The project targets colorectal cancer, where WNT pathway mutations occur in over 90 percent of cases and drive both tumor initiation and chemotherapy resistance. Work will focus on improving potency, selectivity, drug-like properties (ADMET and pharmacokinetics), and in vivo efficacy through animal model studies to evaluate effects on tumor growth, pharmacokinetics, and systemic toxicity. This Phase I SBIR award supports preclinical development activities necessary to advance lead compounds toward investigational new drug-enabling studies.

Performance takes place in Miami, Florida, with a period of performance ending August 31, 2027. The award is a Project Grant, the assistance type for SBIR Phase I funding under the Cancer Treatment Research program.

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer in the united states, with a poor clinical outcome in its advanced form. Mutations in genes encoding components of the WNT signaling pathway (APC and â- catenin) occur in over 90% of all crcs. WNT signaling is highly evolutionary conserved as a regulator of development and stem cell maintenance. Genetic mutations that activate WNT signaling contribute to initiation of cancer, and nuclear accumulation of the WNT signaling molecules â- catenin, correlate with poor clinical outcomes, and underlie low survival. Furthermore, WNT signaling fuels cancer stem cells and contribute to chemotherapy resistance, recurrence, and metastasis. Developing WNT signaling inhibitors as anti-cancer agents has been challenging not only because a limited number of "druggable" targets in this signaling transduction network, but also because of severe on-target gastrointestinal (GI) toxicity due to fundamental roles that canonical WNT signaling play in regular tissue homeostasis. BCL-9 proteins (including BCL-9 and BCL- 9L) are important CO-factors of WNT signaling, that are primarily responsible for WNT-dependent oncogenesis but is largely dispensable in physiological setting. Recently we have identified a series of novel WNT inhibitors, such as our lead molecule sstb-178, that inhibit WNT pathway activity by physically disrupting the binding between â-catenin and BCL-9 proteins. This phase i sbir application aims to continue optimizing this series of molecules to improve their potency, selectivity, drug-like (admet/PK) properties, and in vivo efficacy. Animal models are essential for this project because they provide the only physiologically relevant system to evaluate the integrated effects of BCL-9 inhibition on tumor growth, pharmacokinetics, and systemic toxicity. In vivo studies are also necessary to determine whether our compounds can achieve therapeutic efficacy against WNT-driven CRC while minimizing the on-target toxicities that have limited prior WNT pathway inhibitors. We propose two specific aims: specific aim 1: increase the potency and selectivity of sstb-178. Specific aim 2: evaluate drug-like properties and in vivo efficacy of advanced analogs. This phase i application outlines the essential steps in developing small molecule BCL-9 inhibitors for treating WNT-dependent CRC. Stemsynergy therapeutics, INC (ssti) is a biotechnology company whose focus is on the discovery, development, and commercialization of drugs targeting WNT, notch, and MYC signaling pathways, all of which are critical to cancer cell survival. Ssti's expertise on WNT signaling and medicinal chemistry ensures the aims indicated in this phase i proposal are readily achievable. The work proposed here also have broad commercial potential.