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

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/总结特发性肺纤维化 (IPF) 影响美国 10 万人，总发病率每年增加 5% 患有 IPF 的患者的 5 年生存率在 20-40% 之间。然而，临床批准的 IPF 治疗方法可将疾病进展风险降低 50%。尼达尼布是一种血管激酶抑制剂，其作用靶点超过 30 种。激酶包括血小板衍生生长因子受体、成纤维细胞生长因子受体和血管内皮生长因子受体，在临床试验中，尼达尼布 (Nintedanib) 可使 IPF 下降幅度降低 50%。尽管 Esbriet 和 Nintedanib 已上市用于治疗 IPF，但所有患者均取得进展。治疗，发展为需要氧气的晚期疾病，要么死于疾病，要么接受肺因此，非常需要寻找能够预防和逆转纤维化组织的新疗法。进行性 IPF 患者组织中的转录谱已证明主蛋白的显着激活转录调节因子 STAT3 由 SH2-二聚化结构域 (pSTAT3- Y705）。IPF 中的活性 STAT3 与炎症和 ECM 导致的患者生存率低相关。此外，遗传证据表明 IL6（STAT3 激活剂）内的多态性与疾病独立相关我们追求的进展是，靶向 STAT3 将阻断多种促纤维化途径并减少尽管 STAT3 等 TF 是有吸引力的治疗靶点，它们很难用小分子靶向，因为它们缺乏清晰的结合口袋，具有大的表面在阿勒泰地区，这些区域对蛋白质-蛋白质相互作用很重要，并且包含大的本质上无序的结构域。治疗学方面，我们开发了一个平台，可以识别本质上的小结合袋以前不可成药的 TF 中的无序结构域，允许一种针对 STAT3 的新型可成药方法随着有效且高度特异性的 STAT3 抑制剂（STAT3i）的开发，我们完成了计算机模拟。筛选并鉴定出减少 STAT3 DNA 结合的抑制剂。重要的是，这些 STAT3i 的含量极少。 STAT1 抑制活性、低细胞毒性，并能有效抑制 STAT3 靶点和纤维化我们提出了三个目标来识别和表征最有希望的先导基因，并继续努力开发一种基于抑制 STAT3 的可行的 IPF 治疗方法在目标 1 中，我们将测量细胞毒性。在目标 2 中，使用 Altay 的新型 STAT3is 测量一组正常细胞以及测量 STAT3 靶基因抑制。我们将使用我们的先导 STAT3is 进行博莱霉素诱导的 IPF 小鼠研究，在目标 3 中，我们将确定。从 IPF 患者中分离出的精密切割肺切片中 STAT3i 的抗纤维化活性以及细胞因子的测量拟议的研究将确定靶向 STAT3 治疗 IPF 的潜力并指导新的研究。然后，我们将寻求 SBIR 第二阶段资助，其中包括药物治疗。我们针对 IPF 的 STAT3 抑制剂的化学、其他动物研究以及最终的商业化工作。