A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS

项目摘要/摘要：一种新型小分子CX3CR1拮抗剂抑制肿瘤转移 临床前和临床环境中的证据表明，趋化因子参与了转移的肿瘤细胞 疾病传播。我们设计并合成了第一个新颖、有效的小分子CX3CR1 拮抗探头，JMS-17-2。JMS-17-2是一种有效的选择性CX3CR1功能拮抗剂(PERK IC50=0.32 趋化性IC50≤10 NM)。JMS-17-2在体内是有效的，因为它可以有效地阻止肿瘤细胞种植到 在已建立的转移的小鼠模型中，该药物可降低骨骼和延缓转移进展。改进后的 高级领头羊JMS-FX-68(PERK IC50≤1 NM)显示出令人印象深刻的生存数据，在 活体疗效研究，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： 特定目标1：特定目标1：鉴定一种具有改善肝微粒体稳定性的化合物 保持良好的类药物特性。目标：明确提供类药物的性质和选择性评估 最高级别的类比。 具体目标2：完成对JMS-FX-68的全面描述，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JMS-FX-68的快速后续行动并确定其特征。 目标：明确评估高级临床前随访先导化合物的开发候选标准。 一种转移转移的抑制剂将直接促进临床实践和改善治疗 解决肿瘤扩散问题，这是晚期疾病患者死亡的直接原因。的协同效应 CX3CR1拮抗剂和化疗药物预计将阻止CTCs进入避难所 从骨髓中提取。有证据表明，CX3CR1拮抗作用延伸到肿瘤指征，如乳房 腺癌、前列腺癌、上皮性卵巢癌、胰腺癌和胶质瘤。因此，它被设想为 一种治疗转移进展的有效药物将被广泛应用，并具有显著的 对转移性疾病的发病率和死亡率的影响。

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.