Design of novel protease inhibitors to enhance immune checkpoint blockade in cancer therapy

Cancer immunotherapy has revolutionized the standard of care in many cancers, but still fails to drive a response in many tumor types or is subject to resistance development after initial treatment. Both resistance and a lack of initial response are in part mediated by down regulation of tumor antigen presentation via the MHC Class-I complex in tumors that are less responsive to cancer immunotherapy. Hence approaches that increase MHC-I surface expression, and tumor antigen presentation could improve the response rates to therapies such as immune checkpoint inhibitors. We discovered a novel means of increasing MHC-I antigen presentation via inhibition of an aspartyl protease. Protease inhibition increases b2-microglobulin levels, surface MHC-I complexes, and antigen presentation in cancer cell lines. Molecular dynamics and docking studies led to the identification of a series of non-peptidomimetic protease inhibitors. The grant aims to continue optimization of the chemical series towards more potent, drug-like inhibitors and use a series of in vivo studies to inform potential biomarkers to support early clinical development for the approach.