The development of a transcriptional inhibitor for lung fibrosis.

肺纤维化转录抑制剂的开发。

基本信息

批准号：
10489942
负责人：
Ali Rayet Ozes
金额：
$ 29.91万
依托单位：
ALTAY THERAPEUTICS, INC.
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：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10489942
关键词：
Affect Air Pollution Animals Area Binding Binding Sites Biological Assay Bleomycin C57BL/6 Mouse California Cell-Mediated Cytolysis Cells Cicatrix Clinical Clinical Trials Collagen DNA Binding DNA Binding Domain Development Dimerization Disease Disease Progression Dose Endothelial Growth Factors Receptor Enzyme-Linked Immunosorbent Assay Extracellular Matrix FDA approved Fibroblast Growth Factor Receptors Fibroblasts Fibrosis Gene Expression Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Transcription Grant Heterogeneity Hydroxyproline IL6 gene Immune In Vitro Incidence Inflammation Interleukin-6 Lead Left Life Lung Lung Transplantation Lung diseases MMP9 gene Measures Mesenchymal Stem Cells Methods Modeling Molecular Mus Myoblasts Myofibroblast Nodule Normal Cell Outcome Oxygen Oxygen Therapy Care Pathway interactions Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Pirfenidone Platelet-Derived Growth Factor Receptor Play Property Prophylactic treatment Proteins Pulmonary Fibrosis Research Personnel Role STAT1 gene STAT3 gene San Francisco Series Slice Small Business Innovation Research Grant Smoking Stains Structure of parenchyma of lung Surface Survival Rate Testing Therapeutic Tissues Toxic effect Transforming Growth Factor beta United States Universities Vascular Endothelial Growth Factors Virus Diseases Western Blotting advanced disease aged base commercialization cytokine cytotoxicity disorder risk drug development efficacy study fibrotic lung idiopathic pulmonary fibrosis in silico in vivo indium-bleomycin inhibitor knock-down lead candidate nanomolar nintedanib novel novel therapeutic intervention prevent prognostic protein protein interaction repaired response screening simulation small hairpin RNA small molecule therapeutic target transcription factor translational impact treatment response

Affect Air Pollution Animals Area Binding Binding Sites Biological Assay Bleomycin C57BL/6 Mouse California Cell-Mediated Cytolysis Cells Cicatrix Clinical Clinical Trials Collagen DNA Binding DNA Binding Domain Development Dimerization Disease Disease Progression Dose Endothelial Growth Factors Receptor Enzyme-Linked Immunosorbent Assay Extracellular Matrix FDA approved Fibroblast Growth Factor Receptors Fibroblasts Fibrosis Gene Expression Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Transcription Grant Heterogeneity Hydroxyproline IL6 gene Immune In Vitro Incidence Inflammation Interleukin-6 Lead Left Life Lung Lung Transplantation Lung diseases MMP9 gene Measures Mesenchymal Stem Cells Methods Modeling Molecular Mus Myoblasts Myofibroblast Nodule Normal Cell Outcome Oxygen Oxygen Therapy Care Pathway interactions Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Pirfenidone Platelet-Derived Growth Factor Receptor Play Property Prophylactic treatment Proteins Pulmonary Fibrosis Research Personnel Role STAT1 gene STAT3 gene San Francisco Series Slice Small Business Innovation Research Grant Smoking Stains Structure of parenchyma of lung Surface Survival Rate Testing Therapeutic Tissues Toxic effect Transforming Growth Factor beta United States Universities Vascular Endothelial Growth Factors Virus Diseases Western Blotting advanced disease aged base commercialization cytokine cytotoxicity disorder risk drug development efficacy study fibrotic lung idiopathic pulmonary fibrosis in silico in vivo indium-bleomycin inhibitor knock-down lead candidate nanomolar nintedanib novel novel therapeutic intervention prevent prognostic protein protein interaction repaired response screening simulation small hairpin RNA small molecule therapeutic target transcription factor translational impact treatment response

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项目摘要

Abstract/Summary Idiopathic Pulmonary Fibrosis (IPF) affects 100,000 people in the US with total incidences to increase 5% every year. The 5-year survival rate of patients suffering from IPF is between 20-40%. Esbriet and Nintedanib are clinically approved treatments for IPF. Esbriet reduces risk of disease progression by 50% however, the mechanism of action is currently unknown. Nintedanib is an angiokinase inhibitor that targets more than 30 kinases including platelet-derived growth factor receptor, fibroblasts growth factor receptor and vascular endothelial growth factor receptor and in clinical trials Nintedanib reduced the decline of IPF by 50% after one year of treatment. Although Esbriet and Nintedanib are marketed to treat IPF, all patients progress despite therapy, develop advanced disease requiring oxygen and either succumb to the disease or undergo lung transplantation. Therefore, finding new treatments that both prevent and reverse fibrotic tissue are in great need. Transcriptional profiles in progressive IPF patient tissues have demonstrated significant activation of the master transcriptional regulator STAT3 determined by increased phosphorylation in SH2-dimerization domain (pSTAT3- Y705). Active STAT3 in IPF correlated with poor patient survival driven by inflammation and ECM. Furthermore, genetic evidence shows polymorphisms within IL6, STAT3 activator, was independently associated with disease progression. We hypothesize that targeting STAT3 will block multiple profibrogenic pathways and reduce inflammation and collagen accumulation in the lung. Although TFs like STAT3 are attractive therapeutic targets, they are challenging to target with small molecules because they lack clear binding pockets, have large surface areas important for protein-protein interactions and contain large intrinsically disordered domains. At Altay Therapeutics, we developed a platform that enables identification of small binding pockets within intrinsically disordered domains in previously undruggable TFs, allowing a novel druggable approach for targeting STAT3 with specific and development of potent and highly specific STAT3 inhibitors (STAT3i). We completed in-silico screening and identified inhibitors that reduced STAT3 DNA binding. Importantly, these STAT3i had minimal STAT1 inhibitory activity, low cytotoxicity and demonstrated potent inhibition of STAT3 targets and fibrosis genes. We propose three aims to identify and characterize the most promising lead and continue our efforts to develop a viable treatment for IPF based on inhibiting STAT3. In Aim 1, we will measure cellular cytotoxicity in a panel of normal cells as well as measure STAT3 target gene inhibition with Altay’s novel STAT3is. In Aim 2, we will carry out bleomycin induced IPF mouse studies with our lead STAT3is. In Aim 3, we will determine antifibrotic activity of STAT3i in precision cut lung slices isolated from IPF patients as well as measure cytokine secretion. The proposed studies will establish the potential for targeting STAT3 in treating IPF and guide new therapeutic strategies in this setting. We will then pursue an SBIR phase 2 grant that will include medicinal chemistry efforts, additional animal studies and ultimately commercialization of our STAT3 inhibitor for IPF.

摘要/摘要特发性肺纤维化（IPF）在美国影响100,000人，总发病率每增加5％年。患有IPF的患者的5年生存率在20-40％之间。 Esbriet和Nintedanib是临床批准的IPF治疗方法。埃斯布里特（Esbriet）将疾病进展的风险降低了50％，但是作用机理目前尚不清楚。 Nintedanib是一种血管蛋白酶抑制剂，靶向30多个激酶包括血小板衍生的生长因子受体，成纤维细胞生长因子受体和血管内皮生长因子受体和在临床试验中，nintedanib在一次后降低了IPF的下降50％治疗年份。尽管Esbriet和Nintedanib销售以治疗IPF，但所有患者都会进步治疗，发展需要氧气的晚期疾病，要么屈服于该疾病或经历肺移植。因此，寻找预防和反向纤维化组织的新治疗方法非常需要。进行性IPF患者组织中的转录曲线已显示出主人的显着激活转录调节剂STAT3通过SH2-二级域中的光态化确定（PSTAT3-- Y705）。 IPF中的活性STAT3与注射和ECM的患者生存驱动不良相关。此外，遗传证据表明，IL6中的多态性STAT3激活剂与疾病独立相关进展。我们假设靶向STAT3将阻止多个能络途径并减少肺部炎症和胶原蛋白积累。尽管像STAT3这样的TF是有吸引力的治疗靶标的他们对用小分子的靶向挑战，因为它们缺乏明显的结合口袋，表面较大对蛋白质蛋白质相互作用重要的区域，并包含大型固有无序结构域。在Altay 治疗剂，我们开发了一个平台，可以在本质上识别小型绑定袋以前不可用的TF中受干扰的域名具有特定的和高度特异性的STAT3抑制剂（STAT3I）的发展。我们完成了Silico 筛选并鉴定出降低STAT3 DNA结合的抑制剂。重要的是，这些STAT3I的最低 STAT1抑制活性，低细胞毒性并显示出对STAT3靶标的潜在抑制作用和纤维化基因。我们提出三个目标，以识别和表征最有前途的铅，并继续我们的努力基于抑制STAT3，为IPF开发可行的治疗方法。在AIM 1中，我们将测量细胞细胞毒性一个正常细胞和测量STAT3靶基因抑制Altay的新型STAT3IS。在AIM 2中，我们将使用铅STAT3I进行博来霉素诱导的IPF小鼠研究。在AIM 3中，我们将确定从IPF患者分离的精确切割肺切片中Stat3i的抗纤维化活性以及测量细胞因子分泌。拟议的研究将确定针对STAT3治疗IPF的潜力并指导新的在这种情况下的治疗策略。然后，我们将为SBIR 2阶段拨款提供，其中包括医学化学工作，其他动物研究以及最终对IPF的STAT3抑制剂进行商业化。