Frontiers in Medicinal Chemistry

Volume: 1

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

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

Pp: 3-27 (25)

DOI: 10.2174/978160805204210401010003

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 osteoblasts, while detailing the structure-based design and screening-based lead discovery of Src inhibitors to be developed as therapeutic agents for bone disease.


Keywords: Src, Src inhibitor, protein kinase, SH2, SH3, osteoporosis, bone, structure-based drug design

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