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

基本信息

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
项目类别：
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

项目摘要

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）：早期黑色素瘤通常可以通过手术切除治愈；然而，晚期黑色素瘤总是对现有的化疗药物产生耐药性。尽管经过数十年的广泛研究，达卡巴嗪 (DTIC) 仍然是治疗恶性黑色素瘤的金标准，但它可以使不到 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整体假设来解决这个重大问题，即我们最近发现的有效微管蛋白抑制剂可以有效规避多药耐药性（MDR），并通过与创新的可生物降解纳米颗粒药物输送/靶向策略相结合，它们可以成为一种有效的药物改善恶性黑色素瘤的治疗。我们的理由是，这些化合物的 IC50 值在低纳摩尔范围内，并且可以比高剂量 DTIC 更好地抑制体内黑色素瘤生长。与紫杉醇类似，它们的作用是破坏微管形成并诱导癌细胞凋亡。但与紫杉醇不同的是，它们能有效克服 P-糖蛋白 (Pgp) 介导的多药耐药性 (MDR)，并且非常适合进行结构修饰以进行进一步的临床开发。与目前处于临床试验阶段的同类化合物（例如CA-4和ABT-751）相比，这些化合物具有一些明显的优势。我们的目标是（1）在计算机建模的辅助下合成一组集中的噻唑类似物； (2)开发基于纳米颗粒的最佳药物递送方法，并通过黑色素瘤细胞表面过度表达的受体选择性地靶向黑色素瘤肿瘤，以大幅减少剂量并最大限度地减少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： (1) 优化分子结构，提高效力和水溶性，同时保持抗 MDR 的有效性； (2) 体外筛选合成的抗MDR黑色素瘤化合物并明确其作用机制； (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针对 MDR 黑色素瘤的高效噻唑类似物以及相关的基于纳米颗粒的药物递送/靶向策略，以更有效地治疗恶性黑色素瘤，无论是作为单一药物还是与现有药物组合。