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

用于治疗癌症的Notch1选择性小分子抑制剂的开发

• 批准号: 10325091
• 负责人: William Russell Guerrant
• 金额: $ 94.56万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325091
• 关键词: Adverse effects; Aftercare; Animal Model; Animals; Binding; Biological Availability; Canis familiaris; Cell Line; Cells; Chemotherapy and/or radiation; Clinic; Clinical; Complex; Data; Development; Diagnosis; Dose; Dose-Limiting; Drug Kinetics; Esophageal Adenocarcinoma; Esophagectomy; Euthanasia; Evaluation; Exhibits; Formulation; Gastrointestinal tract structure; Generations; Genetic Transcription; Goals; Growth; Guidelines; Incidence; Intestines; Lead; Life; Malignant Neoplasms; Maximum Tolerated Dose; Monitor; Monoclonal Antibodies; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Oral; Pathologic; Patients; Phase; Positioning Attribute; Process; Property; Protocols documentation; Rattus; Recovery; Recurrence; Risk; Rodent; Role; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; Specificity; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Treatment outcome; Validation; base; cancer therapy; chemotherapy; clinical candidate; clinical investigation; experience; gamma secretase; improved; in vivo; inhibitor/antagonist; intestinal homeostasis; lead candidate; new therapeutic target; notch protein; novel; paralogous gene; patient derived xenograft model; pre-clinical; preclinical development; preclinical safety; programs; research and development; response; safety study; small molecule inhibitor; standard of care; stem; targeted treatment; therapy outcome; treatment response; tumor; tumor growth; tumor xenograft; tumorigenesis

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.

摘要 食管腺癌（EAC）的发病率在过去的40年中增加了两倍，但总体而言， 由于晚期诊断、转移和标准治疗后的高复发率， 化疗标准治疗（新辅助化疗、放疗或两者同时进行， 食管切除术）仅达到20%的响应率，而80%的患者仍然反应不良。最近， 我们已经表明Notch 1信号传导的异常激活与不良的治疗反应相关， 结果表明，EAC患者和EAC肿瘤依赖于持续的Notch 1活性。绝大多数 抑制Notch的研发工作主要集中在γ分泌酶抑制剂（GSI）上， 蛋白质，并因此导致显著的剂量限制性毒性，极大地阻碍了它们迄今为止的临床应用。 因此，对于针对Notch 1依赖性癌症的靶向疗法存在显著未满足的临床需求， 作为EAC。StemSynergy Therapeutics已经确定了一个一流的抑制剂系列， Notch 1转录复合物和限制转录下游效应的Notch 1信号。我们有 证明只有Notch 1依赖性EAC细胞系对我们的抑制剂敏感，这阻断了细胞的生长。 EAC患者来源的异种移植肿瘤。我们进一步改进了药代动力学和特异性， 领先的临床候选物SSTK-302，它是一种高效和选择性的Notch 1抑制剂，可抑制EAC 体内肿瘤生长。此外，SNO 3 -302具有有希望的ADME性质、高口服生物利用度和最大的生物利用度。 重要的是-避免了GSI的剂量限制性毒性。本直接第二阶段提案旨在确定 本发明的目的是为了将新的Notch 1抑制剂推进临床，从而评估SST-302的临床前安全性。