Development of the Next Generation of FABP5 Inhibitors to Treat Prostate Cancer

项目摘要 尽管抗雄激素和紫杉烷类药物治疗取得了进展，但前列腺癌（PC）往往成为 去势抵抗性转移性无法治愈因此，迫切需要发展小说 治疗转移性PC。脂质信号传导和代谢是PC转移的主要驱动力， 为治疗干预提供了理想的靶点。然而，脂质信号传导系统的治疗性开发是不可能的。 由于存在多种脂质代谢酶和核受体， 必须同时瞄准这些系统。脂肪酸结合蛋白5（FABP5）是一种细胞内载体 将生物活性脂质运送到核受体，从而激活基因转录程序， 肿瘤生长和转移。FABP5在正常前列腺中不表达，但高度上调 晚期转移性PC我们的小组已经获得了初步数据，表明FABP5是 对于将由多种胞质到核受体产生的促肿瘤发生脂质递送到 促进PC转移。这将FABP5定位为PC脂质信号传导网络中的重要节点，并将其定位为一个重要的信号传导通路。 对于治疗转移性PC的治疗剂的开发是有吸引力的靶点。尽管有相当大的希望 FABP5抑制剂作为潜在的PC治疗剂，有效的和选择性的抑制剂尚未出现。主要 该提案的目的是开发和优化新的有效的和选择性的FABP5抑制剂。拟议 一个多学科项目将由一个具有计算机辅助药物方面专门知识的高素质小组执行 设计、药物化学和PC生物学。目标1将利用基于结构的药物设计和迭代 化学合成方法来鉴定和优化FABP5抑制剂的效力和选择性。目标2将 采用稳健的体外抑制剂测试平台，包括评估抑制剂效力，功效， 在PC细胞系和非转化细胞中的选择性、稳定性和细胞毒性。目标3将评估 候选抑制剂的小鼠模型的PC，包括一种新的基因工程小鼠模型， 雄激素依赖性和去势抵抗性PC。我们还将评估FABP5抑制剂的疗效， 用作单一疗法并与FDA批准的疗法组合。成功完成 拟议的研究将导致开发优化的FABP5抑制剂支架， 后期IND使能研究和最终临床部署。

Project Summary Despite advances in anti-androgen and taxane-based therapies, prostate cancer (PC) often becomes castration-resistant, metastatic, and incurable. Consequently, there is an urgent need to develop novel interventions to treat metastatic PC. Lipid signaling and metabolism are major drivers of PC metastasis and present ideal targets for therapeutic intervention. However, therapeutic exploitation of lipid signaling systems is hampered by the existence of multiple lipid metabolizing enzymes and nuclear receptors, which would necessitate targeting these systems in parallel. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that shuttles bioactive lipids to nuclear receptors, thereby activating gene transcription programs that enhance tumor growth and metastasis. FABP5 is not expressed in the normal prostate but becomes highly upregulated in advanced metastatic PC. Our group has obtained preliminary data demonstrating that FABP5 is indispensable for the delivery of pro-tumorigenic lipids produced by multiple cytosolic to nuclear receptors to promote PC metastasis. This positions FABP5 as an essential node in a PC lipid signaling network and an attractive target for the development of therapeutics to treat metastatic PC. Despite the considerable promise of FABP5 inhibitors as potential PC therapeutics, potent and selective inhibitors have yet to emerge. The major goal of this proposal is to develop and optimize novel potent and selective FABP5 inhibitors. The proposed multidisciplinary project will be carried out by a highly qualified team with expertise in computer-aided drug design, medicinal chemistry, and PC biology. Aim 1 will leverage structure-based drug design and iterative chemical synthesis approaches to identify and optimize FABP5 inhibitors for potency and selectivity. Aim 2 will employ a robust in vitro inhibitor testing platform including assessments of inhibitor potency, efficacy, selectivity, stability, and cytotoxicity in PC cell-lines and non-transformed cells. Aim 3 will assess the efficacy of candidate inhibitors in mouse models of PC, including a novel genetically engineered mouse model of androgen-dependent and castration-resistant PC. We will also assess the efficacy of FABP5 inhibitors when used as monotherapies and in combination with FDA approved therapeutics. Successful completion of the proposed studies will lead to the development of optimized FABP5 inhibitor scaffolds that can be advanced to late stage IND-enabling studies and eventual clinical deployment.