Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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 and Tomi K. Sawyer

Volume 8, Issue 23, 2002

Page: [2049 - 2075] Pages: 27

DOI: 10.2174/1381612023393323

Price: $65


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

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy