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.

项目摘要/弃权 特发性肺纤维化（IPF）是一种慢性进行性纤维性肺炎的特定形式 在没有任何已知原因的情况下，以肺部内形成疤痕组织的特征。 IPF是一个 毁灭性疾病的预后不良，中位生存时间为2 - 4年。 IPF的自然历史是 诊断后，异质和大多数患者遵循临床过程缓慢下降。但是，情节 急性呼吸忧虑是由少数族裔经历的。 目前，有两种由FDA批准的药物用于治疗IPF，Boehringer Ingelheim's Nintedanib和Roche的Pirfenidone。两种药物仅适度缓慢地发育于IPF肺中的疤痕组织 患者。但是，由于它们仅用于减慢 患者肺功能下降。因此，为IPF开发新疗法有很大的未满足 可以最小化并有可能扭转疾病进程的患者。此外，许多患者 患有严重的共同性19感染有合并症，随后患上肺纤维化疾病1和 Wnt/β-catenin信号的激活与通气诱导的肺纤维化2有关。 IPF是由肺泡上皮细胞（AEC）造成的疾病，随后的异常修复和 与成纤维细胞和肌纤维细胞灶的形成的间质细胞激活。很好 记载Wnt/β-catenin信号在AEC的生存，迁移和增殖中很重要 成纤维细胞中活化的Wnt/β-catenin信号传导增加了迁移，增殖和细胞外基质（例如， 胶原蛋白）生产。然而，β-catenin信号传导在纤维化中的作用似乎遵循“ Goldilocks”模型，即 β-catenin信号传导太少 在AT2中，细胞促进上皮 细胞死亡，从而加剧 肺损伤和纤维化，而 异常高的β-catenin 信号增强纤维化 通过纤维增殖的表型， 迁移和激活。 此外，“好”的命运 与“不良”β-catenin信号传导是 由β-catenin的差异决定 共激活因子使用率（图1）3。 因此，安全调制 Wnt/β-catenin信号传导非常 吸引人的治疗策略 治疗肺纤维化。迄今为止， 没有这样的分子 调节的目标药物 Wnt/β-catenin信号传导和 差异Kat3（即CBP和 p300）用于IPF的共激活因子使用 临床试验。 拟议的研究计划 概述了 电位和高度特异性的小分子，口服可用的CBP/β-catenin拮抗剂，[3+2] -517。这个领导 化合物和候选药物显示出在博霉素诱导的小鼠纤维化模型中有希望的活性 口服时。拟议的研究集中于[3+2] -517的体内评估中的重点 肺纤维化并开发出高度和收敛的比例，以[3+2] -517进行服务 作为GLP/GMP生产API的基础，用于毒理学研究和临床批次 人类1期试验。 “好的” ß-cat信号传导 （p300/ß-cat） “坏的” ß-cat信号传导 （CBP/ß-cat） “坏的” ß-cat信号传导 （CBP/ß-cat） 图1。肺损伤，修复和纤维化期间ß-catenin信号传导的模型。修改的 来自Cara J. Gottardi和MelanieKönigshoff的人物； Am J Respir Crit Care Med 2013 187566-568。