USA flag logo/image

An Official Website of the United States Government

Osteoporosis Screen for Praja 1 E3 Ligase Inhibitors

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
71092
Program Year/Program:
2004 / SBIR
Agency Tracking Number:
AG025568
Solicitation Year:
N/A
Solicitation Topic Code:
N/A
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: 2004
Title: Osteoporosis Screen for Praja 1 E3 Ligase Inhibitors
Agency: HHS
Contract: 1R43AG025568-01
Award Amount: $149,800.00
 

Abstract:

DESCRIPTION (provided by applicant): 0steoporosis represents a major challenge to the maintenance of health and quality of life in an aging population. Among the most promising and least exploited therapeutic interventions are those treatments designed to increase bone density. The selection and validation of targets that can be manipulated to achieve this anabolic effect depends on an increasing amount of information relating to bone formation. A novel area for drug discovery - protein homeostatic regulation via ubiquitin pathway enzymes -- has recently been demonstrated to have relevance to the search for anabolic osteoporosis drugs. Prajal, a RING-finger E3 ubiquitin ligase, has been found to catalyse ubiquitination and, subsequently, induce proteasomal degradation of Dlxin-1, a coactivator of the transcriptional activator DIx5. DIx5 is associated with programmed bone formation. Thus, selective inhibitors of this E3 ligase are hypothesized to increase bone density. In Phase I, it is proposed to establish a yeast-based screening assay for inhibitors of Prajal. Essential components of the E3 system (Prajal) will be cloned and expressed in S. cerevisiae, along with human Dlxin-1 linked to p53, and a reporter construct that monitors p53 activity (beta-galactosidase activation). The reconstructed E3 ligase function and reporter system will then be configured and validated as a high throughput screen for inhibitors of Prajal-mediated Dlxin-1 ubiquitination. Collections of plant and marine organism extracts, along with a small compound collection, will be screened for potent inhibitors of Prajal E3 ubiquitin ligase activity. In Phase II, fractionation of active extracts will be guided by the assay, to identify active principles. Novel pure compounds arising from this effort will be considered as development candidates for osteoporosis. The modular assay construction format will permit evaluation of other E3s that are associated with a variety of diseases.

Principal Investigator:

Michael R. Mattern
6106446974
mattern@progenra.com

Business Contact:


6106446974
Small Business Information at Submission:

PROGENRA, INC.
271 GREAT VALLEY PARKWAY, SUITE 300 MALVERN, PA 19355

EIN/Tax ID: 061660578
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No