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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/概要特发性肺纤维化（IPF）影响美国100，000人，总发病率每增加5% 年IPF患者的5年生存率为20- 40%。Esbriet和Nebriet是临床批准的IPF治疗。Esbriet将疾病进展的风险降低了50%，作用机制目前尚不清楚。Neptin是一种血管激酶抑制剂，靶向30多个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。内皮生长因子受体和在临床试验中，在一次给药后，年治疗。尽管Esbriet和Nestrial已上市用于治疗IPF，但所有患者均出现进展，治疗，发展需要氧气的晚期疾病，要么死于疾病，要么接受肺移植因此，非常需要找到既能预防又能逆转纤维化组织的新治疗方法。进行性IPF患者组织中的转录谱已经证明了主转录因子的显著激活。转录调节因子STAT 3通过增加SH 2-二聚化结构域（pSTAT 3- Y705）。IPF中的活性STAT 3与炎症和ECM导致的患者生存率差相关。此外，委员会认为，遗传学证据显示，IL-6，STAT 3激活剂，内的多态性与疾病独立相关进展我们假设靶向STAT 3将阻断多种促纤维化途径，炎症和肺中胶原蛋白的积累。虽然TF如STAT 3是有吸引力的治疗靶点，它们对于小分子靶向是具有挑战性的，因为它们缺乏清晰的结合口袋，具有大的表面，区域对蛋白质-蛋白质相互作用很重要，并且包含大的内在无序结构域。在阿勒泰在治疗学方面，我们开发了一个平台，能够识别内在的小结合口袋，在以前不可用的TF中的无序结构域，允许一种新的靶向STAT 3的可药用方法具有特异性和开发有效和高度特异性的STAT 3抑制剂（STAT 3 i）。我们完成了计算机模拟筛选并鉴定减少STAT 3 DNA结合的抑制剂。重要的是，这些STAT 3 i具有最小的 STAT 1抑制活性，低细胞毒性，并表现出对STAT 3靶点和纤维化的有效抑制基因.我们提出了三个目标，以确定和描述最有希望的铅，并继续努力，开发基于抑制STAT 3的可行的IPF治疗方法。在目标1中，我们将测量细胞毒性，一组正常细胞以及用Altay的新型STAT 3 is测量STAT 3靶基因抑制。在目标2中，我们将用我们的前导STAT 3 1进行博来霉素诱导的IPF小鼠研究。在目标3中，我们将确定 STAT 3 i在从IPF患者分离的精确切割肺切片中的抗纤维化活性以及测量细胞因子分泌物拟议的研究将确定靶向STAT 3治疗IPF的潜力，并指导新的治疗方法。在这种情况下的治疗策略。然后，我们将寻求SBIR第2阶段赠款，将包括药物化学工作，额外的动物研究和最终的商业化，我们的STAT 3抑制剂的IPF。