Discovery of Novel Thiazole Analogs for Treating Malignant Melanoma

描述(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抗药性。尽管经过了几十年的广泛研究，达卡巴津(DTIC)仍然是治疗恶性黑色素瘤的黄金标准，但它在不到5%的患者中提供了完全缓解。随着美国黑色素瘤发病率的迅速上升，迫切需要开发出对这种疾病更有效的新的治疗方案。我们的目标是通过检验我们最近发现的有效微管蛋白抑制剂可以有效地规避多药耐药(MDR)的总体假设来解决这一重大问题，并通过与创新的可生物降解纳米颗粒药物传递/靶向策略相结合，它们可以成为改进恶性黑色素瘤治疗的有效药物。我们的理论基础是，这些化合物的IC50值在低纳摩尔范围内，在体内抑制黑色素瘤肿瘤生长的效果明显好于高剂量DTIC。它们通过破坏微管形成和诱导癌细胞凋亡来发挥作用，这与紫杉醇类似。但与紫杉醇不同的是，它们有效地克服了P-糖蛋白(Pgp)介导的多药耐药(MDR)，并且非常容易进行结构修饰，以用于进一步的临床开发。与目前临床试验中的类似化合物(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)在计算机模拟的辅助下合成一组有针对性的噻唑类似物；(2)开发一种基于纳米颗粒的最佳给药方法，并通过黑色素瘤细胞表面过表达的受体选择性地靶向黑色素瘤肿瘤，以显著减少剂量并将系统给药相关的潜在副作用降至最低。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，同时保持抗MDR的有效性；(2)在体外筛选抗MDR黑色素瘤的合成化合物并确定其作用机制；以及(3)开发基于纳米颗粒的药物输送和靶向策略，以实现选定类似物的有效体内活性。我们的成果将是开发几种针对耐多药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输送/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联合使用。 与公共卫生相关：目前还没有治疗恶性黑色素瘤的根治方法；可用的治疗方法旨在减缓疾病的传播和缓解症状。在这笔赠款中，我们建议开发新型微管蛋白抑制剂，我们最近发现这些药物有可能成为治疗恶性黑色素瘤的更具选择性和更有效的治疗方法。本文提出的研究旨在验证我们的假设，即这些化合物可以有效地规避多药耐药(MDR)问题，并通过开发合适的基于纳米颗粒的药物传递/靶向策略，为进一步的临床开发提供基础。

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. PUBLIC HEALTH RELEVANCE: Currently there is no curative therapy for malignant melanoma; available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to develop novel classes of tubulin inhibitors that we recently discovered as potential more selective and curative therapy to treat malignant melanoma. Studies proposed herein are designed to test our hypothesis that these compounds can effectively circumvent multidrug resistance (MDR) problems, and by developing suitable nanoparticle-based drug delivery/targeting strategies, they can provide the groundwork for further clinical development.