Targeting Protein Kinases for Bone Disease: Discovery and Development of Src Inhibitors

Title: Targeting Protein Kinases for Bone Disease: Discovery and Development of Src Inhibitors

Volume: 8 Issue: 23

Author(s): Chester A. Metcalf III, Marie Rose van Schravendijk, David C. Dalgarno and Tomi K. Sawyer

Affiliation:

Keywords: Src inhibitor, protein kinase, osteoporosis, structure-based drug design

Abstract: The dynamic and highly regulated processes of bone remodeling involve two major cells, osteoclasts and osteoblasts, both of which command a multitude of cellular signaling pathways involving protein kinases. Of the possible kinases in these cells, Src tyrosine kinase stands out as a promising therapeutic target for bone disease as validated by Src knockout mouse studies and in vitro cellular experiments, suggesting a regulatory role for Src in both osteoclasts (positive) and osteoblasts (negative). Advances in structural studies involving both Src and non-Src family kinases, in activated and unactivated protein states, have uncovered key binding site interactions that have led to the design of potent Src inhibitors. The lead compounds originate from a variety of synthetic templates and have demonstrated nM potency in enzymatic / binding assays and efficacy in animal models of bone disease. This review will provide a current understanding of critical Src signalling pathways in osteoclasts and osteobla sts, while detailing the structure-based design and screening-based lead discovery of Src inhibitors to be developed as therapeutic agents for bone disease.

Cite this article as:

Metcalf III A. Chester, van Schravendijk Rose Marie, Dalgarno C. David and Sawyer K. Tomi, Targeting Protein Kinases for Bone Disease: Discovery and Development of Src Inhibitors, Current Pharmaceutical Design 2002; 8 (23) . https://dx.doi.org/10.2174/1381612023393323