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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43HL160312-01A1
Agency Tracking Number: R43HL160312
Amount: $334,008.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NHLBI
Solicitation Number: PA21-259
Timeline
Solicitation Year: 2021
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-03-05
Award End Date (Contract End Date): 2023-02-28
Small Business Information
3904 CHAPMAN CT
Altadena, CA 91001-3871
United States
DUNS: 117327743
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 OMAR HAFFAR
 (415) 314-7542
 okhaffar@wolfenet.com
Business Contact
 DAVID HORNE
Phone: (626) 808-1396
Email: davidhorne997@yahoo.com
Research Institution
N/A
Abstract

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.

* Information listed above is at the time of submission. *

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