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...