Immunotherapy using biological agents such as anti-PD1 antibody has revolutionized cancer treatment. Nevertheless, patient response has been highly variable, with many patients showing no response. Although the precise mechanism of resistance is unknown, the complex immunosuppressive tumor milieu necessitates development of additional therapeutic agents to potentiate active drugs and expand the scope of the revolutionary cancer immunotherapy. Regulatory T cells (Tregs) present in tumors dampen the anti-tumor activities of effector T cells and are correlated with poor prognosis. Therefore, depletion of Tregs or impairment of Treg function is considered an attractive therapeutic approach. USP7, a deubiquitylase (DUB) implicated as a critical node in several cancer signaling pathways, is essential for maintaining Treg function, and Treg specific deletion of USP7 results in impaired Treg functions and lethal autoimmunity. Progenra has identified selective small molecule USP7 inhibitors that were subsequently lead optimized and evaluated in ADME/PK studies. Potent, selective and irreversible USP7 inhibitors have been shown to impair Treg functions and exhibit powerful anti-tumor activity against syngeneic lung tumor models in immunocompetent mice. In addition, Progenra's USP7 inhibitors synergize with anti-PD1 antibody and cancer vaccines. These studies suggest that USP7 inhibitors alone or in combination can improve the efficacy and expand the scope of cancer immunotherapy
Citation Format: Suresh Kumar, Jian Wu, Liqing Wang, Jack Wang, Ivan Sokirniy, Hui Wang, Glen Fegley, Joseph Weinstock, Michael Mattern, Wayne W. Hancock. Potent and selective small molecule USP7 inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B042.
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