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USP34 as a novel target for treatment of idiopathic pulmonary fibrosis

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
96300
Program Year/Program:
2010 / SBIR
Agency Tracking Number:
HL096155
Solicitation Year:
N/A
Solicitation Topic Code:
NHLBI
Solicitation Number:
N/A
Small Business Information
PROGENRA, INC.
271A GREAT VALLEY PKWY 271A GREAT VALLEY PKWY MALVERN, PA 19355-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2010
Title: USP34 as a novel target for treatment of idiopathic pulmonary fibrosis
Agency: HHS
Contract: 1R43HL096155-01A1
Award Amount: $265,823.00
 

Abstract:

DESCRIPTION (provided by applicant): Aberrant overactivation of WNT signaling appears to play a major role in Idiopathic Pulmonary Fibrosis (IPF). Inhibitors of overactivated WNT signaling are candidates for therapy of IPF. USP34, a novel de-ubiquitylating enzyme, has been identified as an IPF target in the WNT/(-catenin pathway. It interacts with Axin and is required to de-ubiquitylate Axin, allowing it to go to the nucleus where it increases (-catenin signaling. Cellular validation experiments have demons trated that USP34 regulates WNT positively via nuclear localization of (-catenin. As WNT signaling is elevated in IPF, a USP34 inhibitor would decrease signaling and have a potentially therapeutic effect. Progenra has developed a novel isopeptidase assay p latform for measuring DUB activity, and the work proposed here will utilize this assay to discover inhibitors of USP34 by high throughput screening. First, the assay will be configured for USP34 in a 384 well plate format. Next, it will be employed to scre en three small molecule libraries - the ChemDiv Protease Library (2000 compounds), the Maybridge HitFinder diversity library (14,000 compounds), and the DiverSet Library (20,000 compounds) - for potent and selective inhibitors of USP34. The efficacy of sel ected hits will be evaluated in a fibrosis cell-based model of WNT signaling and in cytotoxicity and cellular proof of concept assays. In later stages, lead compounds will be evaluated in in vivo models (bleomycin treatment of mice) and pharmacokinetics st udies. The commercial goal is a pharmaceutical agent active against IPF. PUBLIC HEALTH RELEVANCE: The WNT/(-catenin signaling pathway has been linked to various human diseases, including cancer and Idiopathic Pulmonary Fibrosis (IPF). For these dis eases, inhibitors of WNT signaling are potentially useful as therapeutic agents. Progenra proposes to collaborate with academic experts in the WNT pathway and lung fibrosis to discover inhibitors of an enzyme called USP34, which acts to increase WNT signal ing in IPF. Inhibitors of USP34 will be identified in high throughput screening using Progenra's assay technology and evaluated for preclinical development as therapeutic agents to treat IPF.

Principal Investigator:

Seth Goldenberg
6106446974
GOLDENBERG@PROGENRA.COM

Business Contact:

Michael Mattern
mattern@progenra.com
Small Business Information at Submission:

PROGENRA, INC.
271A GREAT VALLEY PKWY 271A GREAT VALLEY PKWY MALVERN, PA 19355

EIN/Tax ID: 106166057
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No