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.

项目摘要 尽管抗雄激素和基于紫杉烷的疗法取得了进步，但前列腺癌（PC）经常变为 cast割，转移和无法治愈。因此，迫切需要开发小说 处理转移性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， 目的是治疗干预的理想目标。但是，脂质信号系统的治疗剥削是 由于存在多种脂质代谢酶和核受体而受到阻碍，这将 需要并行针对这些系统。脂肪酸结合蛋白5（FABP5）是细胞内载体 这将生物活性脂质穿向核受体，从而激活基因转录程序，以增强 肿瘤生长和转移。 Fabp5在正常前列腺中没有表达，但高度上调 在高级转移PC中。我们的小组获得了初步数据，表明Fabp5是 不可或缺的是由多个胞质到核受体产生的促肿瘤脂质到 促进PC转移。这将FabP5定位为PC脂质信号网络中的必需节点和 开发用于治疗转移性PC的疗法的有吸引力的靶标。尽管有很大的希望 FABP5抑制剂作为潜在的PC疗法，有效和选择性抑制剂尚未出现。专业 该提案的目标是开发和优化新型有效和选择性的FABP5抑制剂。提议 多学科项目将由一支高素质的团队进行，具有计算机辅助药物的专业知识 设计，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 化学合成方法以识别和优化FABP5抑制剂以提高效力和选择性。 AIM 2意志 采用强大的体外抑制剂测试平台，包括评估抑制剂效力，功效， PC细胞线和未转化的细胞中的选择性，稳定性和细胞毒性。 AIM 3将评估 小鼠PC模型中的候选抑制剂，包括一种新型的基因工程小鼠模型 依赖雄激素和cast割的PC。当我们还将评估Fabp5抑制剂的功效 用作单一疗法，并与FDA认可的治疗剂结合使用。成功完成 拟议的研究将导致开发优化的FABP5抑制剂支架，可以将其提升到 晚期辅助研究和最终的临床部署。