The ubiquitin-proteasome system (UPS) is implicated in many disease states including cancer, neurodegenerative disorders, immune dysfunction, cachexia, and cardiovascular and metabolic diseases. While the discovery of small molecules that modulate UPS function has the potential for widespread clinical application, the lack of appropriate physiologically relevant and selective high-throughput screening (HTS) assays has significantly hindered the drug discovery process in this field. Utilizing our expertise in assay development, we have configured proprietary deubiquitylase (DUB) screening platforms and employed them to screen our diverse chemical space. Progenra has discovered selective USP7 inhibitors that demonstrate efficacy in a number of p53-positive and p53-negative animal tumor models. An interesting finding is that USP7 inhibitors block cancer growth in immunocompetent mice; these molecules impair Treg functions, thereby promoting T effector-mediated anti-tumor activity. In addition to their immune mediated antitumor role, the USP7 inhibitors have also demonstrated direct anti-tumor activity in several models. These unexpected findings indicate that USP7 is an important node in cancer and a compelling target for tumor therapy. USP7 inhibitors could be combined with other cancer immunotherapies to achieve durable clinical responses.

Selective deubiquitylase inhibitors for cancer immunotherapy

251st National Meeting (2016)

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