Discovery of chemical probes for uveal melanoma

描述（申请人提供）：目前迫切需要开发治疗眼部高度恶性葡萄膜黑色素瘤的新疗法。葡萄膜黑色素瘤患者在诊断后1-2年内死亡，尽管目前的传统治疗方法包括眼球摘除、放射疗法和化疗。缺氧通过激活血管生成、细胞运动和转移以及缺氧环境下对生长的代谢适应来驱动肿瘤进展，是癌细胞对放疗和化疗产生抗性的主要因素。缺氧激活缺氧诱导因子（HIF）家族的转录因子，诱导编码促血管生成因子和糖酵解酶的基因表达，这些基因是肿瘤生长和肿瘤侵袭所必需的。基于这些发现，我们提出了一个中心假设，即缺氧的发生和HIF通路的激活在眼部肿瘤的生长和扩散中起着关键作用，并且使用小分子抑制剂靶向治疗该通路将抑制眼部肿瘤的生长和转移。我们已经生成了大量的初步数据来验证这一概念。我们发现，我们的铅探针（KCN1）是一种有效的眼部葡萄膜黑色素瘤体内生长（肿瘤大小减少70%）及其转移到肝脏（转移数量减少50%）的抑制剂，同时耐受性非常好。本提案的总体目标是完善我们开发的新型HIF通路抑制剂（HPI）化学探针的结构，优化其效力和药理学特性，从而确定1- 2个临床先导探针，这些探针将准备通过NCI NExT项目在恶性葡萄膜黑色素瘤患者中进行ind指导的药理学和毒理学1期临床试验。我们的多学科团队在化学探针开发的主要方面拥有专业知识，并将项目任务划分为以下目标：在一级和二级分析中筛选母体化合物的类似物，以识别和确认具有更高效力和溶解度的化学探针（目标1）；筛选优化探针的类似物，以改进药理学和配方开发（目标2）；并确定优化后的铅探针在小鼠原位葡萄膜黑色素瘤模型中的抗肿瘤功效（Aim 3）。

DESCRIPTION (provided by applicant): There is an urgent need to develop novel therapies for patients with highly malignant uveal melanomas in the eye. Patients with uveal melanoma die within 1-2 years of diagnosis despite current conventional therapies, including eye enucleation, brachotherapy and chemotherapy. Hypoxia drives tumor progression by activating angiogenesis, cell motility and metastasis, as well as metabolic adaptation to growth under a hypoxic environment and is a major factor in the resistance of cancer cells to radio- and chemotherapies. Hypoxia activates transcription factors of the Hypoxia-Inducible Factor (HIF) family that induce the expression of genes that encode pro-angiogenic factors and glycolytic enzymes essential for tumor growth and favor tumor invasion. Based on these findings, we formulated the central hypothesis that development of hypoxia and activation of the HIF pathway play a critical role in ocular cancer growth and spread, and that therapeutic targeting of this pathway using small molecule inhibitors will inhibit ocular tumor growth and metastasis. We have generated substantial preliminary data validating this concept. We show that our lead probe (KCN1) is a potent inhibitor of the in vivo growth of uveal melanoma in the eye (70% tumor size reduction) and its metastasis to the liver (50% reduction in number of metastases), while being extremely well tolerated. The overall goals of this proposal are to refine the structur of the novel HIF pathway inhibitor (HPI) chemical probes we developed, optimize their potency and pharmacological properties, leading to the identification of 1- 2 clinical lead probes that wil be ready to undergo IND-directed pharmacology and toxicology towards phase 1 clinical testing in patients with malignant uveal melanoma through the NCI NExT program. Our multi- disciplinary team has expertise in major aspects of chemical probe development and will divide the project tasks into the following aims: screening analogs of the parent compound in primary and secondary assays to identify and confirm chemical probes with improved potency and solubility (Aim 1); screening analogs of the optimized probes for improved pharmacology and formulation development (Aim 2); and determine the anti- tumor efficacy of the optimized lead probe(s) in orthotopic uveal melanoma models in mice (Aim 3).