Targeting Protein Kinases for Bone Disease: Discovery and Development of Src Inhibitors
Pp. 3-27 (25)
Chester A. Metcalf, Marie Rose van Schravendijk, David C. Dalgarno and Tomi K. Sawyer
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 osteoblasts, while detailing the structure-based design and screening-based lead discovery of Src inhibitors to be developed as therapeutic agents for bone disease.
Src, Src inhibitor, protein kinase, SH2, SH3, osteoporosis, bone, structure-based drug design
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge MA 02139-4234, USA