Discovery of Novel Thiazole Analogs for Treating Malignant Melanoma

发现用于治疗恶性黑色素瘤的新型噻唑类似物

• 批准号: 8589375
• 负责人: WEI LI
• 金额: $ 29.79万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589375
• 关键词: ABT-751; Address; Adverse effects; Antineoplastic Agents; Apoptosis; Binding; Blood Vessels; Cell Cycle; Cell surface; Cells; Clinical; Clinical Trials; Colchicine; Computer Simulation; Dacarbazine; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Excision; FDA approved; Goals; Gold; Grant; Human; Imidazole; Immunotherapeutic agent; In Vitro; In complete remission; Incidence; Inhibition of Cell Proliferation; Inhibitory Concentration 50; Life; Lung; MSH receptor; Mediating; Melanoma Cell; Microtubules; Modeling; Modification; Molecular Models; Molecular Structure; Multi-Drug Resistance; Multidrug Resistance Inhibition process; Mutation; Neoplasm Metastasis; Outcome; P-Glycoprotein; Paclitaxel; Particle Size; Patients; Peptides; Pharmaceutical Preparations; Relapse; Reporting; Research; Resistance; Site; Skin Cancer; Solubility; Specificity; Staging; Symptoms; Testing; Thiazoles; Time; Toxic effect; Tubulin; United States; Work; Xenograft Model; analog; aqueous; base; cancer cell; chemotherapeutic agent; controlled release; design; drug distribution; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; meetings; melanocyte; melanoma; molecular modeling; nanoparticle; novel; polymerization; public health relevance; receptor; response; small molecule; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): Early stage melanoma can usually be cured by surgical removal; however, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of extensive research, dacarbazine (DTIC) remains the gold standard for treating malignant melanoma, yet it provides complete remission in fewer than 5% of patients. With the rapidly rising incidence of melanoma in the United States, there is an urgent need to develop novel treatment options that will be more effective for this disease. Our goal is to address this significant problem by testing our overall hypothesis that our recently discovered potent tubulin inhibitors can effectively circumvent multidrug resistance (MDR), and by combining with innovative biodegradable nanoparticle-based drug delivery/targeting strategies, they can become an effective agent for improved treatment of malignant melanoma. Our rationale is that these compounds have IC50 values in the low nanomolar range and can inhibit melanoma tumor growth in vivo significantly better than high-dose DTIC. They work by disrupting microtubule formation and inducing cancer cell apoptosis, similar to that of Taxol. But unlike Taxol, they effectively overcome P- glycoprotein (Pgp) mediated multidrug resistance (MDR) and are very amenable to structural modification for further clinical development. Compared with similar compounds currently in clinical trials (e.g., CA-4 and ABT-751), these compounds have some distinct advantages. Our objectives are to (1) synthesize a focused set of thiazole analogs aided by computer modeling; and (2) develop an optimal nanoparticle based drug delivery approach and selectively target melanoma tumors via over-expressed receptors on melanoma cell surface to substantially reduce the dose and minimize potential side effects associated with systematic administration. We will meet our goal and objective by accomplishing the following specific aims: (1) Optimize molecular structures for improved potency and aqueous solubility while maintaining effectiveness against MDR; (2) Screen synthesized compounds against MDR melanoma in vitro and define their mechanism of action; and (3) Develop nanoparticle based drug delivery and targeting strategies for efficient in vivo activity of selected analogs. Our outcome will be the development of several highly efficacious thiazole analogs against MDR melanoma and the associated nanoparticle based drug delivery/targeting strategies for a more effective treatment of malignant melanoma, either as a single agent or in combination with existing drugs.

描述（由申请人提供）：早期黑素瘤通常可以通过手术切除治愈;然而，晚期黑素瘤总是对现有化疗药物具有耐药性。尽管数十年的广泛研究，达卡巴嗪（DTIC）仍然是治疗恶性黑色素瘤的金标准，但它提供了不到5%的患者完全缓解。随着美国黑色素瘤发病率的迅速上升，迫切需要开发对这种疾病更有效的新治疗方案。 我们的目标是通过测试我们的总体假设来解决这一重大问题，即我们最近发现的有效的微管蛋白抑制剂可以有效地规避多药耐药（MDR），并通过与创新的基于生物可降解纳米颗粒的药物递送/靶向策略相结合，它们可以成为改善恶性黑色素瘤治疗的有效药物。我们的理由是，这些化合物具有低纳摩尔范围的IC 50值，并且可以比高剂量DTIC更好地抑制体内黑色素瘤肿瘤生长。它们通过破坏微管形成和诱导癌细胞凋亡来起作用，类似于紫杉醇。但与紫杉醇不同，它们有效地克服了P-糖蛋白（Pgp）介导的多药耐药（MDR），并且非常适合于进一步临床开发的结构修饰。与目前临床试验中的类似化合物（例如，CA-4和ABT-751），这些化合物具有一些明显的优点。 我们的目标是（1）通过计算机建模辅助合成一组集中的噻唑类似物;和（2）开发最佳的基于纳米颗粒的药物递送方法，并通过黑色素瘤细胞表面上过表达的受体选择性地靶向黑色素瘤肿瘤，以大幅降低剂量并最小化与系统给药相关的潜在副作用。我们将通过实现以下具体目标来实现我们的目标和目的：（1）优化分子结构，以提高效力和水溶性，同时保持对MDR的有效性;（2）筛选体外抗MDR黑素瘤的合成化合物，并确定其作用机制;（3）开发基于纳米颗粒的药物递送和靶向策略，以实现所选类似物的有效体内活性。 我们的成果将是开发几种高效的噻唑类似物对MDR黑色素瘤和相关的纳米颗粒为基础的药物递送/靶向策略，更有效地治疗恶性黑色素瘤，无论是作为一个单一的代理商或与现有的药物组合。