Small Molecule Inhibitors Targeting OTUD4-CD73 Interaction for Immune-Cold Tumors

Application

This technology introduces small molecule inhibitors, ST80 and Z22, to disrupt the protein-protein interaction (PPI) between OTUD4 and CD73. These inhibitors enhance tumor immunogenicity by reducing CD73 stabilization, improving the immune response in triple-negative breast cancer (TNBC) and other immune-cold tumors.

Key Benefits

• ST80 and Z22 uniquely target the OTUD4-CD73 interaction, reducing CD73 protein levels and overcoming immunosuppressive mechanisms.
• Enhance the efficacy of existing immunotherapies by restoring cytotoxic T-cell activity.
• Provide a novel treatment strategy for patients with limited options, such as those with TNBC who do not respond to standard therapies.

Market Summary

Immune-cold tumors like TNBC are characterized by poor immune responses and limited treatment options. These tumors account for a significant portion of breast cancers and disproportionately affect certain populations, such as African American women and BRCA mutation carriers. Current therapies often fail to address the immunosuppressive environment, highlighting the need for innovative solutions that can rejuvenate immune system engagement and improve patient outcomes.

Technical Summary

ST80 and Z22 are novel small molecule inhibitors designed to block the OTUD4-CD73 interaction. By destabilizing CD73, these compounds reduce its accumulation and restore immune responses, as demonstrated in preclinical models. ST80 and Z22 increase CD8+ T-cell activity, suppress tumor growth, and show promise in combination with PD-L1 blockade therapies like durvalumab. This dual-action approach enhances tumor immunogenicity and combats resistance to immune checkpoint inhibitors.

Development Stage

• Demonstrated efficacy in vitro and in vivo in breast cancer models.
• Lead compounds ST80 and Z22 have completed initial development, with ongoing efforts to optimize and expand their therapeutic potential.

Publication Wan, Y., Zhu, Y., Bahar, I., & Banerjee, A. (2024). Pharmacological Suppression of the OTUD4/CD73 Proteolytic Axis Revives Antitumor Immunity Against Immune-Suppressive Breast Cancers. Journal of Clinical Investigation. https://www.jci.org/articles/view/176390