Project Summary Inflammation and ulceration of mucosal tissue, called mucositis, is a severe side effect of many common treatments in oncology, including chemo- and radiotherapy. Mucositis development is costly to the health care system and can lead to poorer outcomes for patients. Mucositis of the mouth and esophagus, called oral mucositis, is particularly common in head and neck cancer patients receiving radiation therapy, where roughly 80% of patients develop this side effect. Treating oral mucositis remains a large clinical unmet need with no FDA approved treatments. Using Sinopia Biosciences’ computational platform, we identified a target class and an associated small molecule for preventing and/or treating mucositis. The target class has an established safety profile in patients with solid tumors. In two studies with the acute radiation-induced hamster model of oral mucositis, we observed compelling results that oral administration of the compound significantly decreased the duration of ulcerative mucositis and in some animals completely prevented the development of ulcers. The observed effect size was as large or larger than other compounds currently in the clinic tested in the same model. The test compound is a pan-inhibitor of several targets in the target class, each with multiple binding domains. In Phase I, we identified the specific domain within this target class that most safely contributes to mucositis amelioration. Selective inhibition of this domain retains the efficacy of the pan-inhibitor, but avoids the general toxicity issues seen with pan-inhibition. In this Phase II proposal, we will develop a novel orally bioavailable compound that selectively inhibits this specific target domain. We will then characterize this new compound in the fractionated radiation model of oral mucositis mucositis to advance the program towards the clinic.