Evaluation of a Small-Molecule Inhibitor of DDR2 as a Drug in Treatment of Osteoarthritis
Abstract
Topic Area: Arthritis and Post-Traumatic Osteoarthritis. Existing drugs for the treatment of osteoarthritis (OA) primarily treat the pain associated with a rapidly deteriorating joint. Unfortunately, no amount of analgesic or agent designed to lubricate the joint can replace the cartilage lost to the degenerative process in the development of OA. However, one of the unique characteristics of the development of OA is the delay between an initiating event and the onset of the pain, lack of mobility, and reduced quality of life associated with advanced OA. This relatively long progressive period provides an opportunity for early intervention with a pharmacological agent to delay or prevent joint destruction. For the development of disease-modifying OA drugs (DMOADs), we need to identify potential therapeutic targets. The results from several independent research groups demonstrate that a cell surface receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), may be an ideal target for the development of DMOADs. DDR2 induces matrix metalloproteinase 13 (MMP-13) in chondrocytes leading to development of OA. In line with this observation, the genetic removal of DDR2 gene can prevent joints from being destructed in mouse models of OA. Therefore, biological reagents that can inhibit the activity of DDR2 may be used as drugs to treat the disease. In this project, we plan to test whether a novel small molecule inhibitor of DDR2 can significantly delay the progressive destruction of articular cartilage in a mouse model of trauma-induced OA. If so, a novel formulation of such a DDR2 inhibitor could be developed for evaluation in human clinical trials. DDR2 inhibitors have the potential to become blockbuster drugs for the treatment of human OA, with the possibility of receiving the highly desirable disease-modifying label from the Food and Drug Administration.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810097
Entities
People
- Yefu Li
Organizations
- Harvard University
- United States Army