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

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

Journal Name: Current Pharmaceutical Design

Volume 8 , Issue 23 , 2002

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.

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

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Article Details

VOLUME: 8
ISSUE: 23
Year: 2002
Page: [2049 - 2075]
Pages: 27
DOI: 10.2174/1381612023393323
Price: $58

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