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.

项目概要/摘要 特发性肺纤维化（IPF）是慢性进行性纤维化间质性肺炎的一种特殊形式 以在没有任何已知原因的情况下在肺内形成疤痕组织为特征。IPF是一种 预后不良的毁灭性疾病，中位生存时间为2-4年。IPF的自然史是 异质性，大多数患者在诊断后遵循缓慢下降的临床过程。然而， 急性呼吸道恶化，是由一个显着的少数经历。 目前有两种药物被FDA批准用于治疗IPF，勃林格殷格翰的 尼达尼布和罗氏的吡非尼酮。两种药物均仅适度减缓IPF肺部瘢痕组织的发展 患者然而，两者都无法逆转甚至阻止疾病进展，因为它们只是起到减缓疾病进展的作用。 患者的肺功能下降。因此，开发新的IPF治疗方法的需求很大， 患者可以最低限度地稳定并可能逆转疾病的进程。此外，许多患者 严重COVID-19感染伴合并症，随后发生肺纤维化疾病1， Wnt/β-连环蛋白信号传导的激活与呼吸机诱导的肺纤维化相关2。 IPF是一种由肺泡上皮细胞（AEC）损伤引起的疾病，随后发生异常修复， 间充质细胞过度活化，形成成纤维细胞和成肌纤维细胞灶。公 证明Wnt/β-catenin信号传导在AEC的存活、迁移和增殖中是重要的， 成纤维细胞中激活的Wnt/β-连环蛋白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-连环蛋白信号传导在纤维化中的作用似乎遵循“金发女孩”模型， 当β-连环蛋白信号 在AT 2细胞中促进上皮 细胞死亡从而加剧 肺损伤和纤维化，而 异常高β-catenin 信号传导增强纤维化 表型通过纤维增生， 迁移和激活。 此外，命运的“好” 与“坏的”β-连环蛋白信号相比， 由β-连环蛋白差异决定 共活化剂的使用（图1）3. 因此，安全调制 Wnt/β-catenin信号是一个非常重要的 吸引人的治疗策略， 治疗肺纤维化。到目前为止， 没有这样的分子 靶向药物， Wnt/β-catenin信号传导和 差异Kat 3（即CBP和 p300）共活化剂使用，用于IPF， 临床试验 拟议的研究计划 概述了一个 高效、高特异性小分子，口服，CBP/β-catenin拮抗剂，[3+2]-517。这条线索 化合物和药物候选物在博来霉素诱导的纤维化小鼠模型中显示出有希望的活性 当口服给药时。拟议的研究集中在[3+2]-517逆转晚期的体内评价 肺纤维化，并开发一种高效和收敛的放大合成[3+2]-517， 作为IND毒理学研究用API的GLP/GMP生产基础， 人类1期试验。 “好” CAT信号 (p300/-cat） “坏” CAT信号 (CBP/-cat） “坏” CAT信号 (CBP/-cat） 图1.肺损伤、修复和纤维化过程中β-连环蛋白信号传导的模型。改性 图来自Cara J. Gottardi和Melanie Königshoff; Am J Respir Crit Care Med 2013 187566-568.