Discovery of chemical probes for uveal melanoma

描述(由申请人提供)：眼部高度恶性葡萄膜黑色素瘤患者迫切需要开发新的治疗方法。患有葡萄膜黑色素瘤的患者在确诊后1-2年内死亡，尽管目前的常规治疗包括眼球摘除、睫状体疗法和化疗。低氧通过激活血管生成、细胞运动和转移，以及在低氧环境下对生长的代谢适应来推动肿瘤进展，是肿瘤细胞对放化疗耐药的主要因素。低氧激活低氧诱导因子(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，这些基因对肿瘤生长和肿瘤侵袭是必不可少的。基于这些发现，我们提出了一个中心假设，即低氧的发展和HIF通路的激活在眼癌的生长和转移中起着关键作用，使用小分子抑制剂进行靶向治疗将抑制眼肿瘤的生长和转移。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，我们的先导探针(KCN1)对眼内葡萄膜黑色素瘤的体内生长(肿瘤体积缩小70%)及其向肝脏的转移(转移数目减少50%)是有效的抑制作用，同时具有极好的耐受性。这项建议的总体目标是改进我们开发的新型HIF途径抑制物(HPI)化学探针的结构，优化其效力和药理特性，导致识别1-2个临床领先探针，这些探针将准备好通过NCI NEXT计划对恶性葡萄膜黑色素瘤患者进行IND指导的药理学和毒理学第一阶段临床测试。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，将把项目任务分为以下目标：在一次和二次分析中筛选母体化合物的类似物，以鉴定和确认效力和溶解度更高的化学探针(目标1)；筛选优化的探针的类似物，以改进药理学和配方开发(目标2)；以及确定优化的先导探针(S)在小鼠原位葡萄膜黑色素瘤模型中的抗肿瘤效果(目标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).