Colorectal cancer (CRC) is the second leading cause of cancer death with an estimated 8.7% of cancer-related deaths and about 149,500 new cases of CRC diagnosed in 2021. Although overall mortality from CRC continues to decline, survival remains poor for advanced disease. While chemotherapy is still the mainstay to treat CRC, cancer immunotherapies, immune checkpoint blockades (ICBs) in particular, have achieved unprecedented clinical responses and are revolutionizing cancer treatments. Despite of the tremendous success of cancer immunotherapies, it remains unclear why only a subset of individuals respond to treatment and how to turn non-responders to become responsive. Many combination trial...

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Colorectal cancer (CRC) is the second leading cause of cancer death with an estimated 8.7% of cancer-related deaths and about 149,500 new cases of CRC diagnosed in 2021. Although overall mortality from CRC continues to decline, survival remains poor for advanced disease. While chemotherapy is still the mainstay to treat CRC, cancer immunotherapies, immune checkpoint blockades (ICBs) in particular, have achieved unprecedented clinical responses and are revolutionizing cancer treatments. Despite of the tremendous success of cancer immunotherapies, it remains unclear why only a subset of individuals respond to treatment and how to turn non-responders to become responsive. Many combination trials with PD1/PDL1 inhibitor are being explored in clinic.

Understanding the inflammatory responses and cell death pathways in the tumor microenvironment becomes one of the important research directions to advance cancer immunotherapies. Receptor-interacting protein kinase 1 (RIP) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways. Removal of RIP protein from cancer cells sensitizes them to immunotherapies. Leveraging the Proteolysis targeting chimera (PROTAC) technology, we developed a first-in-class RIP degrader LD4172. In our preliminary study, we showed that LD4172 potently degrades RIP protein in a panel of human cancer cell lines. In a mouse melanoma immunocompetent model, LD4172 significantly synergized with anti-PD1.

In this project, we will continue our medicinal chemistry campaign to improve the potency of RIP degrader and test its efficacy in a panel of preclinical CRC mouse models. Successful completion of this project will lead to the development of not only a chemical probe to interrogate RIP-related biology but also a highly promising therapeutic agent to advance cancer immunotherapies.

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