Novel Orally Available CBP/Beta-Catenin Antagonists to Treat Idiopathic Pulmonary Fibrosis

新型口服 CBP/β-连环蛋白拮抗剂治疗特发性肺纤维化

• 批准号: 10480363
• 负责人: Omar Haffar
• 金额: $ 33.4万
• 依托单位: 3+2 PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480363
• 关键词: AGTR2 gene; Acute; Adenovirus Vector; Affect; Animal Model; Bleomycin; Caring; Cell Death; Cells; Chronic; Cicatrix; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials; Collagen; Continuous Intravenous Infusion; Development; Diagnosis; Disease; Disease Progression; Dose; EP300 gene; Epithelial Cells; Extracellular Matrix; FDA approved; Felis catus; Fibroblasts; Fibrosis; Formulation; Gene Expression; Generations; Grant; Hepatitis C virus; Human; Immune; In Vitro; Injury; Interstitial Pneumonia; Investigation; Japan; Kidney; Lead; Liver; Liver Fibrosis; Lung; Mesenchymal; Minority; Modeling; Mus; Natural History; New Agents; Oral; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Pirfenidone; Population; Preclinical Testing; Production; Prognosis; Pulmonary Fibrosis; Research; Role; SARS-CoV-2 infection; Safety; Signal Transduction; Structure of parenchyma of lung; Technology; Therapeutic; Time; Tissues; Toxicology; Transforming Growth Factor beta; Ventilator; WNT Signaling Pathway; alveolar epithelium; analog; antagonist; base; beta catenin; clinical development; comorbidity; delivery vehicle; design; drug candidate; experience; idiopathic pulmonary fibrosis; improved; in vivo evaluation; indium-bleomycin; injury and repair; interstitial; liver function; lung injury; migration; molecular drug target; mouse model; nano-string; nintedanib; novel; novel therapeutics; phase I trial; potential biomarker; pre-clinical; preclinical study; pulmonary function; repaired; respiratory; scale up; severe COVID-19; small molecule

PROJECT SUMMARY/ABSRACT Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia characterized by the formation of scar tissue within the lungs in the absence of any known cause. IPF is a devastating disease with a poor prognosis and a median survival time of 2–4 years. The natural history of IPF is heterogeneous and most patients follow a slowly declining clinical course after diagnosis. However, episodes of acute respiratory worsening, are experienced by a significant minority. Currently there are two drugs approved by the FDA for the treatment of IPF, Boehringer Ingelheim's nintedanib and Roche's pirfenidone. Both drugs only modestly slow development of scar tissue in lungs of IPF patients. However, neither can reverse nor even halt disease progression, as they merely serve to slow the decline in patients' lung function. Therefore, there is a great unmet need to develop new therapeutics for IPF patients that can minimally stabilize and potentially reverse the course of the disease. Additionally, many patients with severe COVID-19 infections with comorbidities, subsequently develop pulmonary fibrotic disease1 and activation of Wnt/β-catenin signaling is associated with ventilator- induced pulmonary fibrosis2. IPF is a disease caused by injury to alveolar epithelial cells (AECs) with subsequent aberrant repair and over activation of mesenchymal cells with the formation of fibroblastic and myofibroblastic foci. It is well documented that Wnt/β-catenin signaling is important in the survival, migration, and proliferation of AECs and activated Wnt/β-catenin signaling in fibroblasts increases migration, proliferation, and extracellular matrix (e.g. collagen) production. However, the role of β-catenin signaling in fibrosis appears to follow a “Goldilocks” model, where too little β-catenin signaling in AT2 cells promotes epithelial cell death thereby exacerbating lung injury and fibrosis, whereas aberrantly high β-catenin signaling enhances the fibrotic phenotype via fibroproliferation, migration, and activation. Furthermore, the fate of “good” versus “bad” β-catenin signaling is dictated by β-catenin’s differential coactivator usage (Fig. 1)3. Therefore, safe modulation of Wnt/β-catenin signaling is a very appealing therapeutic strategy to treat pulmonary fibrosis. To date, there are no such molecularly targeted drugs that modulate Wnt/β-catenin signaling and differential Kat3 (i.e. CBP and p300) coactivator usage, for IPF in clinical trials. The proposed research plan outlines the development of a potent and highly specific small molecule, orally available, CBP/β-catenin antagonist, [3+2]-517. This lead compound and drug candidate demonstrates promising activity in the bleomycin induced mouse model of fibrosis when dosed orally. The proposed research centers on in vivo evaluation of [3+2]-517 to reverse late stage pulmonary fibrosis and to develop a highly efficient and convergent scale up synthesis for [3+2]-517 to serve as the basis for GLP/GMP production of the API for IND-enabling toxicology studies and clinical batch for the human phase 1 trial. “GOOD” ß-cat signaling (p300/ß-cat) “Bad” ß-cat signaling (CBP/ß-cat) “Bad” ß-cat signaling (CBP/ß-cat) Fig. 1. Model for ß-catenin signaling during lung injury, repair and fibrosis. Modified figure from Cara J. Gottardi and Melanie Königshoff; Am J Respir Crit Care Med 2013 187566-568.

项目总结/ ABSRACT