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

开发下一代治疗前列腺癌的 FABP5 抑制剂

• 批准号: 10092979
• 负责人: Martin Kaczocha
• 金额: $ 67.67万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10092979
• 关键词: Acids; Affinity; Algorithm Design; Ames Assay; Androgen Antagonists; Binding; Biological; Biological Assay; Cancer Biology; Cancer Etiology; Castration; Cells; Cessation of life; Clinical; Computer Assisted; Cytochrome P450; Data; Development; Disease; Docking; Drug Design; Drug Kinetics; Enzymes; FDA approved; Free Energy; Generations; Genetic Transcription; Genetically Engineered Mouse; Goals; Half-Life; Heart; In Vitro; Injections; Intervention; Ion Channel; Lead; Link; Lipids; MYC gene; Malignant neoplasm of prostate; Maps; Metabolism; Metastatic Prostate Cancer; Metastatic to; Molecular; Mus; Neoplasm Metastasis; Nuclear Receptors; Nude Mice; Outcome; Patients; Pharmaceutical Chemistry; Plasma; Positioning Attribute; Preclinical Testing; Production; Prostate; Prostate Cancer therapy; Prostatic; Protein Isoforms; Proteins; Receptor Signaling; Resistance; Signal Transduction; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; United States; advanced prostate cancer; analog; androgen sensitive; base; castration resistant prostate cancer; chemical synthesis; cytotoxicity; design; efficacy testing; fatty acid metabolism; fatty acid-binding proteins; improved; in silico; in vivo; in vivo evaluation; inhibitor/antagonist; intracellular protein transport; lead optimization; lipid transport; men; molecular dynamics; mouse model; multidisciplinary; next generation; novel; pre-clinical; programs; prostate cancer cell line; prostate cancer metastasis; prostate cancer model; receptor; scaffold; screening; subcutaneous; targeted treatment; taxane; therapeutic development; tumor growth; tumorigenic

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.

项目概要 尽管抗雄激素和紫杉烷类疗法取得了进展，但前列腺癌 (PC) 常常变得 去势抵抗、转移且无法治愈。因此，迫切需要开发新颖的 治疗转移性 PC 的干预措施。脂质信号传导和代谢是 PC 转移的主要驱动因素 提出了治疗干预的理想目标。然而，脂质信号系统的治疗利用是 多种脂质代谢酶和核受体的存在阻碍了 需要并行瞄准这些系统。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，增强 肿瘤生长和转移。 FABP5 在正常前列腺中不表达，但会高度上调 在先进的转移性 PC 中。我们小组已获得初步数据证明 FABP5 对于将多个胞质至核受体产生的促肿瘤脂质递送至 促进PC转移。这将 FABP5 定位为 PC 脂质信号网络中的重要节点和 开发治疗转移性 PC 的有吸引力的目标。尽管有相当大的承诺 虽然 FABP5 抑制剂作为潜在的 PC 治疗药物，但有效的选择性抑制剂尚未出现。主要 该提案的目标是开发和优化新型有效且选择性的 FABP5 抑制剂。拟议的 多学科项目将由具有计算机辅助药物专业知识的高素质团队进行 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 化学合成方法来识别和优化 FABP5 抑制剂的效力和选择性。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、功效、 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 将评估以下措施的功效： PC 小鼠模型中的候选抑制剂，包括一种新型基因工程小鼠模型 雄激素依赖性和去势抵抗性PC。我们还将评估 FABP5 抑制剂的功效 用作单一疗法并与 FDA 批准的疗法联合使用。圆满完成了 拟议的研究将导致优化 FABP5 抑制剂支架的开发，该支架可以进一步用于 后期 IND 支持研究和最终临床部署。