Optimization of fibroblast-selective inhibitors of YAP/TAZ as novel therapeutics for Pulmonary Fibrosis

YAP/TAZ 成纤维细胞选择性抑制剂作为肺纤维化新疗法的优化

基本信息

批准号：
10553722
负责人：
Andrew Jon Haak
金额：
$ 61.89万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10553722
关键词：
Accounting Actins Agonist Automobile Driving Biological Assay Cardiovascular system Cell Maintenance Cell Nucleus Cell physiology Cells Cessation of life Chronic Complex Coupled Cytoplasm DRD1 gene Deposition Development Disease Disease Progression Diversity Library Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Drug Targeting Endothelial Cells Endothelium Epithelial Cells Epithelium Europe Extracellular Matrix Fibroblasts Fibrosis Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genes Genetic Transcription Goals Grant Hepatic Homeostasis Human In Vitro Individual Internet Kidney LATS1 gene Lead Lung Lung diseases Mechanical Stress Mediating Metabolic Pathway Modeling Molecular Muscle Nuclear Pathway interactions Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphorylation Play Prevalence Proliferating Property Proteins Pulmonary Fibrosis Rodent Model Role Route Series Signal Transduction Skin Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Tissues Transcriptional Coactivator with PDZ-Binding Motif United States Work analog cell type cofactor differential expression drug discovery effective therapy experimental study high throughput screening idiopathic pulmonary fibrosis improved in vitro activity in vivo in vivo Model inhibitor mortality mouse model novel novel therapeutics programs pulmonary function decline scaffold scale up screening side effect small molecule small molecule inhibitor stem cells therapeutic development therapeutic target therapeutically effective therapy outcome transcription factor treatment strategy

项目摘要

PROJECT SUMMARY Idiopathic pulmonary fibrosis is a chronic, progressive and conclusively fatal disease in which aberrant fibroblast proliferation, contraction, and extracellular matrix (ECM) deposition causes lung function decline. Studies by our group and others, have identified a pivotal role for Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) transcription co-factors in activating fibroblasts to drive fibrosis in the lung. Although these studies highlight the YAP/TAZ transcriptional program as a potential target for drug discovery, the multitude of signaling inputs modulating this pathway, YAP and TAZ ubiquitous expression, and their involvement in a wide array of cell functions, including stem cell maintenance, epithelial and endothelial homeostasis, render them challenging therapeutic targets. Therefore, a treatment strategy targeting YAP/TAZ in fibroblasts selectively over epithelial and endothelial cells would provide a novel avenue to treat IPF. While we have shown that fibroblast-selective inhibition of nuclear localization of YAP/TAZ reverses fibrosis in IPF mouse models using dopamine receptor D1 agonists, challenges in development of such compounds into effective therapies have led us to perform a target-agnostic high-throughput screen, which identified several selective small molecule hit compounds with validated anti-fibrotic activity in cell-based assays. The goal of this phased R61/R33 proposal is to further characterize and optimize our novel fibroblast selective YAP/TAZ inhibitors into potent and selective compounds with validated anti-fibrotic activity in vitro and ex vivo, and with favorable in vitro ADME/PK properties (R61 phase). We will then optimize drug-like in vivo properties for 1-2 lead scaffolds, confirming their anti-fibrotic effects caused by cell type-selective inhibition of YAP/TAZ in in vivo IPF mouse models (R33 phase). Together, the proposed experiments will generate lead molecule(s), which can serve as the basis for an effective therapy to treat IPF patients.

项目概要特发性肺纤维化是一种慢性、进行性且最终致命的疾病，其中异常的成纤维细胞增殖、收缩和细胞外基质（ECM）沉积导致肺功能下降。我们的研究研究小组和其他人已经确定了 Yes 相关蛋白 1 (YAP) 和转录共激活因子的关键作用与 PDZ 结合基序 (TAZ) 转录辅助因子一起激活成纤维细胞以驱动肺部纤维化。虽然这些研究强调 YAP/TAZ 转录程序作为药物发现的潜在靶标，调节该途径的大量信号输入、YAP 和 TAZ 普遍表达及其参与在广泛的细胞功能中，包括干细胞维持、上皮和内皮稳态，他们具有挑战性的治疗目标。因此，选择性靶向成纤维细胞中的 YAP/TAZ 的治疗策略上皮细胞和内皮细胞的治疗将为治疗 IPF 提供新途径。虽然我们已经证明了成纤维细胞选择性抑制 YAP/TAZ 核定位可逆转 IPF 小鼠模型的纤维化多巴胺受体 D1 激动剂，将此类化合物开发成有效疗法的挑战导致我们进行了与目标无关的高通量筛选，确定了几个选择性小分子命中在基于细胞的测定中具有经过验证的抗纤维化活性的化合物。此分阶段 R61/R33 提案的目标是进一步表征和优化我们的新型成纤维细胞选择性 YAP/TAZ 抑制剂，使其成为有效的选择性抑制剂具有经过验证的体外和离体抗纤维化活性以及良好的体外 ADME/PK 特性的化合物（R61 相）。然后，我们将优化 1-2 个先导支架的类药物体内特性，确认它们的抗纤维化作用在体内 IPF 小鼠模型（R33 期）中，YAP/TAZ 的细胞类型选择性抑制引起的效应。一起，拟议的实验将产生先导分子，它可以作为有效治疗的基础治疗 IPF 患者。