The development of a transcriptional inhibitor for lung fibrosis.

肺纤维化转录抑制剂的开发。

• 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
• 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

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.

抽象/总结