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: 10478196
• 负责人: Dennis Liang Fei
• 金额: $ 103.1万
• 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/10478196
• 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; 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