Development of Notch1-selective Small Molecule Inhibitor for the Treatment of Cancer

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ABSTRACT The incidence of esophageal adenocarcinoma (EAC) has tripled over the last 40 years, but five-year overall survival is still poor due to late stage diagnosis, metastasis, and high rates of recurrence after standard chemotherapy. Standard-of-care therapy (neoadjuvant chemotherapy, radiation, or both followed by esophagectomy) achieves only 20% response rates, while 80% of patients remain poorly responsive. Recently, we have shown that aberrant activation of Notch1 signaling correlates with poor therapeutic responses and outcomes in EAC patients and that EAC tumors are dependent upon sustained Notch1 activity. The vast majority of R&D efforts to inhibit Notch have focused on gamma secretase inhibitors (GSIs), which inhibit all Notch proteins, and as a result cause significant dose-limiting toxicity, largely hampering their clinical utility to date. Thus, there is a significant unmet clinical need for targeted therapies against Notch1-dependent cancers such as EAC. StemSynergy Therapeutics has identified a first-in-class inhibitor series that binds and inhibits the Notch1 Transcriptional Complex and limits transcription of downstream effectors of Notch1 signaling. We have demonstrated that only Notch1-dependent EAC cell lines are sensitive to our inhibitors, which blocked the growth of EAC patient-derived xenograft tumors. We further improved pharmacokinetics and specificity to produce our lead clinical candidate SSTN-302, which is a highly potent and selective inhibitor of Notch1 and inhibits EAC tumor growth in vivo. Furthermore, SSTN-302 has promising ADME properties, high oral bioavailability, and most importantly - avoids the dose-limiting toxicity of GSIs. This Direct Phase II proposal seeks to determine the preclinical safety of SSTN-302 for the purposes of advancing a novel Notch1 inhibitor into the clinic.