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

PROJECT SUMMARY/ABSRACTIdiopathic 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 signalingin AT2 cells promotes epithelialcell death thereby exacerbatinglung injury and fibrosis, whereasaberrantly high β-cateninsignaling enhances the fibroticphenotype via fibroproliferation,migration, and activation.Furthermore, the fate of “good”versus “bad” β-catenin signaling isdictated by β-catenin’s differentialcoactivator usage (Fig. 1)3.Therefore, safe modulation ofWnt/β-catenin signaling is a veryappealing therapeutic strategy totreat pulmonary fibrosis. To date,there are no such molecularlytargeted drugs that modulateWnt/β-catenin signaling anddifferential Kat3 (i.e. CBP andp300) coactivator usage, for IPF inclinical trials.The proposed research planoutlines 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.