A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS

一种新型小分子 CX3CR1 拮抗剂可阻止转移

• 批准号: 9340341
• 负责人: Joseph M Salvino
• 金额: $ 82.21万
• 依托单位: ALLIANCE DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340341
• 关键词: Address; Bioavailable; Bone Marrow; Bone Tissue; Breast Adenocarcinoma; Breast Cancer Patient; CRISPR interference; Cancer Patient; Cause of Death; Chemotaxis; Chronic; Clinical; Clinical Trials; DNA Double Strand Break; Data; Development; Disease; Dose; Drug Kinetics; Epithelial; Formulation; Fractalkine; Future; Genes; Genetic Transcription; Glioma; Goals; Hand; Homing; Human; Impairment; Industry Standard; Lead; Left; Liver Microsomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolic; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oral; Ovarian Carcinoma; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Property; Prostate; Pyrroles; Repression; Role; Skeleton; Solid Neoplasm; Therapeutic Agents; Toxicology; Tumor Burden; Validation; advanced disease; analog; base; cancer cell; chemokine; chemokine receptor; clinical practice; design; drug candidate; effective therapy; efficacy study; follow-up; improved; in vivo; inhibitor/antagonist; knock-down; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; oncology; pre-clinical; prevent; research clinical testing; small molecule; survival outcome; synergism; tumor

Project Summary/ Abstract: A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS Evidence in pre-clinical and clinical settings suggests the involvement of chemokines in metastatic tumor cell disease spreading. We have designed and synthesized the first novel, potent, small molecule CX3CR1 antagonist probe, JMS-17-2. JMS-17-2 is a potent selective CX3CR1 functional antagonist (pERK IC50 = 0.32 nM; Chemotaxis IC50 ≤ 10 nM). JMS-17-2 is effective in vivo, as it potently blocks tumor cell seeding to the skeleton and slows metastatic progression in a mouse model of established metastasis. The improved advanced lead, JMS-FX-68 (pERK IC50 ≤ 1 nM) shows impressive survival data in a preliminary 16 week in vivo efficacy study, and importantly appears to demonstrate an effective and safe survival outcome. Specific aims of this proposal are: Specific Aim 1: Specific Aim 1: Identify a compound with improved liver microsome stability while maintaining good drug-like properties. Goal: To clearly provide Drug-like property and selectivity assessment for the top analogs. Specific Aim 2: Complete full characterization of JMS-FX-68 to provide Development Candidate Assessment. Goal: To clearly assess Development candidate criteria for this advanced pre-clinical lead compound. Specific Aim 3: Identification and characterization of a fast follow-up to JMS-FX-68. Goal: To clearly assess Development candidate criteria for an advanced pre-clinical follow-up lead compound. An inhibitor of metastatic dissemination will advance clinical practice and improve therapy by directly addressing tumor spreading, the direct cause of mortality in patients with advanced disease. Synergy of a CX3CR1 antagonist and a chemotherapeutic is expected due to preventing CTCs from entering the sanctuary of the bone marrow. Evidence shows that CX3CR1 antagonism extends to oncology indications such as breast adenocarcinoma, prostate, epithelial ovarian carcinoma, pancreatic cancer, and glioma. Thus, it is envisioned that an efficacious drug to treat metastatic progression would be widely applicable and have a significant impact on the morbidity and mortality associated with metastatic disease.

项目摘要/摘要：一种新型小分子CX 3CR 1拮抗剂阻止转移 临床前和临床环境中的证据表明，趋化因子参与转移性肿瘤细胞 疾病传播。我们已经设计并合成了第一个新的，有效的，小分子CX 3CR 1 拮抗剂探针，JMS-17-2。JMS-17-2是一种有效的选择性CX 3CR 1功能性拮抗剂（pERK IC 50 = 0.32 nM;趋化性IC 50 ≤ 10 nM）。JMS-17-2在体内是有效的，因为它有效地阻断肿瘤细胞向肿瘤细胞的种植。 在已建立转移的小鼠模型中，改进的 先进的铅，JMS-FX-68（pERK IC 50 ≤ 1 nM）显示了令人印象深刻的生存数据，在初步的16周， 体内疗效研究，重要的是似乎证明了有效和安全的生存结果。 这项建议的具体目标是： 具体目标1：具体目标1：鉴定具有改善的肝微粒体稳定性的化合物， 保持良好的药物样性质。目的：明确提供类药性质和选择性评估 对于顶级的类似物。 具体目标2：完成JMS-FX-68的全面表征，以提供开发候选评估。 目标：明确评估这种先进的临床前先导化合物的开发候选标准。 具体目标3：确定和表征JMS-FX-68的快速后续行动。 目的：明确评估高级临床前随访先导化合物的开发候选标准。 转移性播散的抑制剂将通过直接抑制肿瘤细胞的增殖来推进临床实践并改善治疗。 解决肿瘤扩散，晚期疾病患者死亡的直接原因。A的协同作用 CX 3CR 1拮抗剂和化疗药物预期可防止CTC进入保护区 的骨髓。有证据表明，CX 3CR 1拮抗作用可扩展至肿瘤适应症，如乳腺癌 腺癌、前列腺癌、上皮性卵巢癌、胰腺癌和神经胶质瘤。因此，可以设想， 治疗转移性进展的有效药物将是广泛适用的， 对转移性疾病相关发病率和死亡率的影响。