SBIR-STTR Award

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 fibro proliferation, 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"ÃŸ-cat signaling(p300/ß-cat)"Bad"ÃŸ-cat signaling(CBP/ß-cat)"Bad"ÃŸ-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 2013187566-568.

Public Health Relevance Statement:
Project Narrative Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating disease with a poor prognosis and a median survival time of 2-4 years. Treatment options are limited with no drugs available to reverse or even halt disease progression. New agents are urgently needed that can safely ameliorate and reverse established lung fibrosis.

Project Terms:
Affect, Bleomycin, Bleo, Felis catus, Cats, Cats Mammals, Domestic Cats, Feline Species, Felis domestica, Felis domesticus, Felis sylvestris catus, Cell Death, necrocytosis, Cells, Cell Body, Cicatrix, Scars, Clinical Research, Clinical Study, Clinical Trials, Collagen, comorbidity, co-morbid, co-morbidity, Diagnosis, Disease, Disorder, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Epithelial Cells, Extracellular Matrix, Cell-Extracellular Matrix, ECM, Fibroblasts, Fibrosis, Gene Expression, Grant, Human, Modern Man, In Vitro, Japan, Kidney, Kidney Urinary System, renal, Lead, Pb element, heavy metal Pb, heavy metal lead, Liver, hepatic body system, hepatic organ system, Lung, Lung Respiratory System, pulmonary, Mus, Mice, Mice Mammals, Murine, Patients, Phenotype, Production, Lung Tissue Fibrosis, fibrosis in the lung, lung fibrosis, Pulmonary Fibrosis, Research, social role, Role, Safety, Cell Communication and Signaling, Cell Signaling, Intracellular Communication and Signaling, Signal Transduction Systems, Signaling, biological signal transduction, Signal Transduction, Technology, Time, Tissues, Body Tissues, Toxicology, Transforming Growth Factor beta, Bone-Derived Transforming Growth Factor, Milk Growth Factor, Platelet Transforming Growth Factor, TGF B, TGF-beta, TGF-β, TGFbeta, TGFβ, Transforming Growth Factor-Beta Family Gene, indium-bleomycin, In-bleomycin, Generations, Ventilator, beta catenin, Beta Cadherin-Associated Protein, Beta-1 Catenin, CUL-2, PRO2286, β-catenin, Caring, Injury, injuries, Natural History, base, improved, Acute, Chronic, Clinical, repaired, repair, Interstitial Pneumonia, Interstitial Lung Inflammation, Interstitial Pneumonitis, Interstitial Pulmonary Inflammation, Lung Alveolar Epithelia, alveolar epithelium, lung function, pulmonary function, liver function, fibrotic liver, hepatic fibrosis, Liver Fibrosis, Disease Progression, analog, Lung damage, pulmonary damage, pulmonary injury, pulmonary tissue damage, pulmonary tissue injury, lung injury, Esbriet, Pirfenidone, Therapeutic, Investigation, Immunes, Immune, Oral, Clinic, respiratory, experience, interstitial, Animal Models and Related Studies, model of animal, model organism, Animal Model, novel, Lung Parenchyma, Lung Tissue, Structure of parenchyma of lung, Modeling, Phase I Clinical Trials, Early-Stage Clinical Trials, Phase 1 Clinical Trials, phase I protocol, small molecule, AGTR2, AT2, AGTR2 gene, E1A Binding Protein p300, EP300, KAT3B, histone acetyltransferase p300, p300, EP300 gene, Dose, Ad vector, Adenoviral Vector, adeno vector, adenovector, Adenovirus Vector, Continuous Intravenous Infusion, Mesenchymal, pre-clinical testing, Preclinical Testing, New Agents, WNT Signaling Pathway, WNT signaling, Development, developmental, Cirrhosis, cirrhotic, pre-clinical, preclinical, preclinical study, pre-clinical study, injury and repair, design, designing, Minority, scale up, Population, migration, novel therapeutics, new drug treatments, new drugs, new therapeutics, new therapy, next generation therapeutics, novel drug treatments, novel drugs, novel therapy, mouse model, murine model, FDA approved, drug candidate, nano-string, nanostring, phase I trial, phase 1 trial, potential biomarker, potential biological marker, Formulation, molecular drug target, molecular pharmacotherapy target, clinical development, Hepatitis C virus, HCV, in vivo evaluation, in vivo testing, idiopathic pulmonary fibrosis, Fibrosing Alveolitis, diffuse interstitial pulmonary fibrosis, severe COVID-19, life-threatening COVID, life-threatening COVID-19, life-threatening SARS-CoV-2, life-threatening coronavirus disease, life-threatening coronavirus disease 2019, life-threatening severe acute respiratory syndrome coronavirus 2, serious COVID, serious COVID-19, serious SARS-CoV-2, serious coronavirus disease, serious coronavirus disease 2019, serious severe acute respiratory syndrome coronavirus 2, severe COVID, severe COVID19, severe SARS-CoV-2, severe coronavirus disease, severe coronavirus disease 19, severe coronavirus disease 2019, severe severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 infection, COVID-19 infection, COVID19 infection, SARS-CoV2 infection, Severe acute respiratory syndrome coronavirus 2 infection, coronavirus disease 2019 infection, infected with COVID-19, infected with COVID19, infected with SARS-CoV-2, infected with SARS-CoV2, infected with coronavirus disease 2019, infected with severe acute respiratory syndrome coronavirus 2, Prognosis, nintedanib, Ofev, antagonist, delivery vehicle, delivery vector