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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

基本信息

批准号：
9887053
负责人：
Martin Kaczocha
金额：
$ 69.6万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
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/9887053
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

项目摘要

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.

项目总结