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/ABSRACT 特发性肺纤维化是慢性进行性纤维化性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是一种 严重疾病，预后差，中位生存期2-4年。IPF的自然历史是 异质性和大多数患者在诊断后遵循缓慢下降的临床病程。然而，几集 急性呼吸恶化是相当少数的人经历的。 目前有两种药物被FDA批准用于治疗IPF，勃林格-英格尔海姆公司 诺替达尼和罗氏的吡非尼酮。两种药物只能适度延缓IPF肺内瘢痕组织的形成 病人。然而，它们既不能逆转疾病的发展，也不能阻止疾病的发展，因为它们只是用来减缓 患者的肺功能下降。因此，开发治疗特发性肺间质纤维化的新疗法是一个尚未得到满足的巨大需求。 患者可以最小限度地稳定并有可能逆转疾病的进程。此外，许多患者 严重新冠肺炎感染并合并疾病，随后发展为肺纤维化1和 Wnt/β-Catenin信号的激活与呼吸机诱导的肺纤维化有关。 IPF是一种由肺泡上皮细胞(AECs)损伤引起的疾病，随后发生异常修复和 间充质细胞过度活化，形成成纤维细胞和肌成纤维细胞灶。这很好 已证实WNT/β-连环蛋白信号在血管内皮细胞的存活、迁移和增殖中起重要作用 成纤维细胞中激活的Wnt/β-catenin信号可促进迁移、增殖和细胞外基质(例如 胶原蛋白)生产。然而，β-连环蛋白信号在肝纤维化中的作用似乎遵循“金发女孩”模型， β-连环蛋白信号太少的地方 在AT2细胞中促进上皮细胞 细胞死亡，从而加剧 肺损伤和纤维化，而 异常高的β-连环蛋白 信号转导增强纤维化 通过纤维增殖的表型， 迁移和激活。 此外，“好”的命运 与“坏的”β-连环蛋白信号相比 由β-连环蛋白的差异决定 共活化剂的使用(图1) 因此，安全调制 WNT/β-连环蛋白信号是一种非常 吸引人的治疗策略 治疗肺纤维化。到目前为止， 在分子上不存在这样的 靶向药物调节 WNT/β-连环蛋白信号转导和 差分Kat3(即CBP和 P300)共激活剂使用，用于IPF中 临床试验。 拟议的研究计划 概述了 强效和高度特异的小分子，口服，CBP/β-连环蛋白拮抗剂，[3+2]-517。这条线索 化合物和候选药物在博莱霉素诱导的小鼠肝纤维化模型中显示出良好的活性 当口服的时候。建议的研究集中在体内评价[3+2]-517以逆转晚期 肺纤维化和发展高效和收敛的放大合成为[3+2]-517服务 作为GLP/GMP生产用于IND毒理学研究和临床批次的原料药的基础 人体试验1期。 “好” ？？CAT信令 (P300/？-CAT) “坏” ？？CAT信令 (CBP/ü-CAT) “坏” ？？CAT信令 (CBP/ü-CAT) 图1.肺损伤、修复和纤维化过程中？？连环蛋白信号的模型。已修改 图片来自Cara J.Gottardi和Melanie Königshoff；Am J Respir Crit Care Med 2013 187566-568.