Immune evasion is a hallmark feature of tumors as they employ various strategies to suppress the immune system's ability to recognize and destroy cancer cells. Significant advances in the understanding of the mechanisms of cancer immune evasion have led to the successful development of immunotherapies that exhibit clinical efficacy against hematological as well as solid tumors. Due to the underlying complexity of cancer immune evasion, however, several different approaches will likely be necessary for effective therapeutic management. Progenra is developing novel small molecule cancer immunotherapeutics by understanding and exploiting the role of ubiquitin in immune regulation. We have identified inhibitors of a deubiquitylase (DUB) that is highly expressed in regulatory T (Tregs) cells and plays a critical role in promoting Treg functions. The unique mechanism of action was demonstrated by a combination of NMR spectroscopy and mass spectrometry. In addition, we have identified inhibitors of an E3 ubiquitin ligase that negatively regulates T-effector cell function. These inhibitors could be combined with other cancer immunotherapies to achieve durable clinical responses.

Targeting ubiquitin pathway enzymes for cancer immunotherapy

253rd National Meeting (2017)

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