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：
10369515
负责人：
Andrew Jon Haak
金额：
$ 64.35万
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/10369515
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 Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs 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 Mus Muscle Nuclear Pathway interactions Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphorylation Play Prevalence 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 base cell type differential expression drug discovery effective therapy experimental study high throughput screening idiopathic pulmonary fibrosis improved in vitro activity in vivo in vivo Model inhibitor 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

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 Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs 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 Mus Muscle Nuclear Pathway interactions Patients Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Phosphorylation Play Prevalence 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 base cell type differential expression drug discovery effective therapy experimental study high throughput screening idiopathic pulmonary fibrosis improved in vitro activity in vivo in vivo Model inhibitor 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

展开

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.

项目摘要特发性肺纤维化是一种慢性，进行性和最终致命疾病，其中成纤维细胞异常增殖，收缩和细胞外基质（ECM）沉积会导致肺功能下降。我们的研究组和其他人已经确定了与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）转录辅助因子激活成纤维细胞以驱动肺中的纤维化。虽然这些研究强调了YAP/TAZ转录程序是药物发现的潜在目标，多种信号输入调节此途径，YAP和TAZ无处不在的表达及其参与在各种各样的细胞功能中，包括干细胞维护，上皮和内皮稳态，渲染他们挑战治疗目标。因此，一种针对成纤维细胞YAP/TAZ的治疗策略选择性地上皮细胞和内皮细胞将提供一种新颖的途径来治疗IPF。虽然我们已经表明成纤维细胞选择性抑制YAP/TAZ的核定位置使用IPF小鼠模型中的纤维化逆转多巴胺受体D1激动剂，这种化合物发展为有效疗法的挑战已导致我们要执行目标高通量屏幕，该屏幕确定了几个选择性的小分子命中在基于细胞的测定中具有验证抗纤维化活性的化合物。该分阶段R61/R33提案的目标是为了进一步表征和优化我们的新型成纤维细胞选择性yap/taz抑制剂具有经过验证的抗纤维化活性的化合物体外和Ex Vivo，并且具有良好的体外ADME/PK特性（R61相）。然后，我们将以1-2的铅支架优化类似药物的体内特性，确认其抗纤维化由细胞类型选择性抑制YAP/TAZ在体内IPF小鼠模型（R33相）中引起的影响。一起，提出的实验将产生铅分子，该分子可以作为有效治疗的基础治疗IPF患者。