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 其特征是在没有任何已知原因的情况下在肺部形成疤痕组织。 IPF 是一个 这是一种毁灭性的疾病，预后不良，中位生存时间为 2-4 年。 IPF 的自然史是 异质性，大多数患者诊断后临床病程缓慢下降。然而，剧集 相当少数人会经历急性呼吸系统恶化。 目前有两种药物获得 FDA 批准用于治疗 IPF，即勃林格殷格翰 (Boehringer Ingelheim) 的 尼达尼布和罗氏的吡非尼酮。这两种药物仅适度减缓 IPF 肺部疤痕组织的发展 患者。然而，它们都不能逆转甚至阻止疾病的进展，因为它们只能减缓疾病的进展。 患者肺功能下降。因此，开发 IPF 新疗法的需求亟待满足 可以最低限度地稳定并有可能逆转疾病进程的患者。另外，很多患者 患有严重的 COVID-19 感染并伴有合并症，随后发展为肺纤维化疾病1并且 Wnt/β-连环蛋白信号传导的激活与呼吸机诱发的肺纤维化相关2。 IPF 是一种由肺泡上皮细胞 (AEC) 损伤以及随后的异常修复和修复引起的疾病。 间充质细胞过度激活，形成成纤维细胞和肌成纤维细胞灶。很好 文献记载，Wnt/β-连环蛋白信号传导对于 AEC 的存活、迁移和增殖非常重要， 成纤维细胞中激活的 Wnt/β-连环蛋白信号传导会增加迁移、增殖和细胞外基质（例如， 胶原蛋白）的生产。然而，β-连环蛋白信号在纤维化中的作用似乎遵循“金发姑娘”模型， β-连环蛋白信号传导太少 AT2细胞中促进上皮细胞 从而加剧细胞死亡 肺损伤和纤维化，而 β-连环蛋白异常高 信号传导增强纤维化 通过纤维增殖的表型， 迁移和激活。 此外，“善”的命运 与“坏”β-连环蛋白信号传导相比 由β-连环蛋白的微分决定 共激活剂的使用（图1）3。 因此，安全调制 Wnt/β-连环蛋白信号传导是一种非常 有吸引力的治疗策略 治疗肺纤维化。迄今为止， 不存在这样的分子 调节的靶向药物 Wnt/β-连环蛋白信号传导和 差分 Kat3（即 CBP 和 p300) 共激活剂的使用，用于 IPF 临床试验。 拟议的研究计划 概述了一个发展 有效且高度特异性的小分子，口服，CBP/β-连环蛋白拮抗剂，[3+2]-517。这导致 化合物和候选药物在博莱霉素诱导的纤维化小鼠模型中表现出有希望的活性 口服给药时。拟议的研究重点是[3+2]-517逆转后期的体内评估 开发一种高效、收敛的放大合成[3+2]-517以服务于肺纤维化 作为用于 IND 毒理学研究和临床批次的 API 的 GLP/GMP 生产的基础 人体 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、修复和纤维化过程中 ß-catenin 信号传导模型。修改的 来自 Cara J. Gottardi 和 Melanie Königshoff 的人物； Am J Respir Crit Care Med 2013 187566-568。