Discovery of Novel Cytotoxic Agents for Advanced Melanoma

描述（由申请人提供）：发现治疗晚期黑色素瘤的新型细胞毒性药物虽然早期黑色素瘤通常可以通过手术切除治愈，但晚期黑色素瘤总是对现有的化疗药物产生耐药性。尽管经过数十年的研究，达卡巴嗪（DTIC）仍然是FDA批准的唯一一种治疗晚期黑色素瘤的药物，但它只能使不到5%的患者完全缓解。随着美国黑色素瘤发病率的迅速上升，迫切需要开发新的化疗药物来治疗这种疾病。我们最近在体外发现了三种有效的抗黑色素瘤先导化合物。与DTIC不同，这些分子不是烷基化剂。最有可能的是，它们干扰了与癌细胞信号通路有关的生长因子和其他分子。最有效的先导化合物的IC50值在亚微摩尔范围内，对癌细胞的选择性超过10倍。与在临床试验中显示出治疗黑色素瘤良好效果的药物索拉非尼相比，这些新化合物更有效，更有选择性。这些化合物的作用机制可能不同于现有的抗癌药物，如DTIC、紫杉醇或索拉非尼。在本提案中，我们计划进行广泛的合成和SAR研究，以进一步优化这些化合物的效力和选择性。我们的中心假设是，我们的先导结构的新类似物可以比临床试验中使用的现有药物具有更好的选择性，同时对黑色素瘤具有更高的效力。我们的具体目标是：(1)合成有针对性的噻唑烷类似物，然后进行广泛的结构活性关系（SAR）研究，以优化先导物；(2)在进行合成和生物学试验的同时，结合生物学和化学的分析技术来研究这些新化合物可能的作用机制并验证其药物靶点。高分辨率魔角旋转核磁共振（HR-MAS NMR）和其他先进的分析技术将以类似于基因组学和蛋白质组学实验的方式用于适应性代谢反应的全球分析。该项目的最终目标是合成和鉴定具有新的作用机制的最有前途的化合物，以进一步在体内发展。公共卫生相关性：目前尚无治疗晚期黑色素瘤的有效疗法；现有的治疗方法旨在减缓疾病的传播并缓解症状。我们在这项拨款中提议合成新型化合物作为潜在的治疗剂。本文提出的研究旨在验证这样一种假设，即这些化合物的活性将提高疗效，并可以被优化，为开发一类新的治疗晚期侵袭性黑色素瘤的药物提供基础。这是一项高风险的创新建议，旨在发现一种非手术手段，为晚期黑色素瘤提供更具选择性和疗效的药物治疗。

DESCRIPTION (provided by applicant): Discovery of Novel Cytotoxic Agents for Advanced Melanoma While melanoma in early stages can usually be cured by surgical removal, melanoma in advanced stages is invariably resistant to existing chemotherapeutic agents. Despite decades of research, Dacarbazine (DTIC) still remains the only FDA approved drug to treat advanced melanoma, yet it only provides complete remission in less than 5% of patients. With the rapidly rising incidents of melanoma in the United States, there is an urgent need to develop novel chemotherapeutic agents for this disease. We recently identified three potent lead compounds against melanoma in vitro. Unlike DTIC, these molecules are not alkylation agents. Most likely they interfere with growth factors and other molecules involved in the cancer cell's signaling pathways. The most potent lead compounds have IC50 values in the sub-micromole range with over 10 fold selectivity against cancer cells. Compared with the drug Sorafenib which showed promising effects for melanoma treatment in clinical trials, these novel compounds are more potent and more selective. The mechanisms of action of these compounds are likely to be different from existing anticancer drugs such as DTIC, Taxol, or Sorafenib. In this proposal, we plan to perform extensive synthesis and SAR studies to further optimize the potency and selectivity of these compounds. Our central hypothesis is that new analogs of our lead structures could achieve better selectivity than existing drugs used in clinical trials, while possessing much higher potency towards melanoma. Our specific aims are: (1) to synthesize focused sets of thiazolidine analogs, followed by extensive structure activity relationships (SAR) studies for lead optimization; (2) parallel to the synthetic efforts and biological testing, to use combinations of analytical techniques in both biology and chemistry to investigate the possible mechanisms of action and verify the drug targets for these novel compounds. High resolution magic angle spinning NMR (HR-MAS NMR) and other advanced analytical techniques will be used for global analysis of adaptive metabolic responses in an analogous fashion to genomics and proteomics experiments. The ultimate goal for this project is to synthesize and identify sets of the most promising compounds having novel mechanisms of actions for further in vivo development. PUBLIC HEALTH RELEVANCE: There is currently no curative therapy for advanced melanoma; available treatments are aimed at slowing the spread of the disease and relieving the symptoms. We proposed in this grant to synthesize novel classes of compounds as potential therapeutic agents. Studies proposed herein are designed to test the hypothesis that the activity of these compounds will have improved efficacy and can be optimized and provide the groundwork for the development of a new class of therapeutic agents to treat advanced aggressive melanoma. This is a high risk, innovative proposal to discover a non-surgical means for a more selective and curative pharmacologic therapy for advanced melanoma.