Discovery of Novel Thiazole Analogs for Treating Malignant Melanoma

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，但它在不到5%的患者中完全缓解。随着美国黑色素瘤发病率的迅速上升，迫切需要开发新的治疗方案，以更有效地治疗这种疾病。我们的目标是通过测试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）的整体假设来解决这个重大问题，并且通过结合创新的可生物降解纳米颗粒为基础的药物递送/靶向策略，它们可以成为改善恶性黑色素瘤治疗的有效药物。我们的基本原理是这些化合物在低纳摩尔范围内具有IC50值，并且可以比高剂量DTIC显著更好地抑制黑色素瘤肿瘤的体内生长。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。但与紫杉醇不同的是，它们可以有效地克服P糖蛋白（Pgp）介导的多药耐药（MDR），并且非常适合进行结构修饰，以便进一步的临床开发。与目前正在临床试验的类似化合物（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重点的噻唑类似物；(2)开发一种基于纳米颗粒的最佳给药方法，通过黑色素瘤细胞表面过表达的受体选择性靶向黑色素瘤肿瘤，从而大幅降低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)优化分子结构以提高效力和水溶性，同时保持抗耐多药的有效性；(2)体外筛选抗MDR黑色素瘤的合成化合物，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，以提高所选类似物的体内活性。我们的研究成果将是开发几种高效的针对耐多药黑色素瘤的噻唑类似物，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，无论是单独使用还是与现有药物联合使用。

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.