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

摘要 食管腺癌(EAC)的发病率在过去40年中增加了两倍，但总体来说 由于晚期诊断、转移和标准治疗后的高复发率，存活率仍然很低。 化疗。标准治疗(新辅助化疗、放疗或两者兼而有之) 食道切除术)的有效率仅为20%，而80%的患者反应仍然较差。最近， 我们已经证明，Notch1信号的异常激活与不良的治疗反应和 EAC患者的预后以及EAC肿瘤依赖于持续的Notch1活性。绝大多数人 抑制Notch的研发工作主要集中在伽马分泌酶抑制剂(GSI)上，GSI可以抑制所有Notch 蛋白质，因此造成显著的剂量限制毒性，很大程度上阻碍了它们迄今的临床应用。 因此，对于Notch1依赖的癌症的靶向治疗存在着重大的未得到满足的临床需求 以EAC的身份。StemSynergy Treateutics公司已经确定了一种一流的抑制剂系列，该系列可以结合和抑制 NOTCH1转录复合体，限制Notch1信号下游效应因子的转录。我们有 显示只有依赖Notch1的EAC细胞系对我们的抑制物敏感，它阻止了生长 来自EAC患者的异种移植瘤。我们进一步改进了药代动力学和特异性，以生产我们的 领先的临床候选SSTN-302，它是一种高效和选择性的Notch1抑制剂，并抑制EAC 肿瘤在体内生长。此外，SSTN-302具有良好的ADME特性、高口服生物利用度和大多数 重要的是-避免了GSI的剂量限制毒性。这项直接第二阶段提案旨在确定 为了将一种新的Notch1抑制剂推向临床，SSTN-302的临床前安全性。

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.