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

项目摘要 尽管在抗雄激素和基于紫杉烷的治疗方面取得了进展，前列腺癌(PC)经常成为 耐阉割，转移，不治之症。因此，迫切需要发展小说 治疗转移性PC的干预措施。脂质信号和代谢是PC转移和 提出治疗干预的理想靶点。然而，脂质信号系统的治疗性开发是 受阻于多种脂质代谢酶和核受体的存在，这将 有必要同时瞄准这些系统。脂肪酸结合蛋白5(FABP5)是细胞内的载体 它将生物活性脂质运送到核受体，从而激活基因转录程序，从而增强 肿瘤的生长和转移。FABP5在正常前列腺中不表达，但高度上调 在晚期转移性PC中。我们小组已经获得了初步数据，表明FABP5是 对于将多个胞质到核受体产生的促肿瘤脂质输送到 促进PC转移。这将FABP5定位为PC脂质信令网络中的基本节点和 为治疗转移性PC的治疗方法的发展提供了有吸引力的靶点。尽管有相当大的承诺 在作为潜在的PC治疗药物的FABP5抑制剂中，还没有出现有效的和选择性的抑制剂。少校 这项建议的目标是开发和优化新的、有效的和选择性的FABP5抑制剂。建议数 多学科项目将由一个在计算机辅助药物方面具有专业知识的高素质团队进行 设计学、药物化学和PC生物学。AIM 1将利用基于结构的药物设计和迭代 识别和优化FABP5抑制剂效力和选择性的化学合成方法。目标2将 采用强大的体外抑制剂测试平台，包括评估抑制剂的效力、有效性、 PC细胞系和未转化细胞的选择性、稳定性和细胞毒性。目标3将评估 PC小鼠模型中的候选抑制剂，包括一种新的基因工程小鼠模型 雄激素依赖和抗去势的PC。我们还将评估FABP5抑制剂的疗效，当 作为单一疗法使用，并与FDA批准的疗法联合使用。圆满完成 拟议的研究将导致优化的FABP5抑制剂支架的开发，这种支架可以推进到 后期启用IND的研究和最终的临床部署。

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.