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Targeting protein kinases for bone disease: discovery and development of Src inhibitors
Chester A Metcalf1, Marie Rose van Schravendijk, David C Dalgarno
1ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. chet.metcalf@ariad.com
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.
Insights
Src tyrosine kinase regulates bone remodeling cells, osteoclasts and osteoblasts. Inhibitors targeting Src signaling pathways show promise for treating bone diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Bone remodeling relies on osteoclasts and osteoblasts, utilizing complex signaling pathways involving protein kinases.
- Src tyrosine kinase (Src) plays a critical regulatory role in both osteoclast (positive) and osteoblast (negative) function.
- Genetic and cellular studies highlight Src as a key therapeutic target for bone diseases.
Purpose of the Study:
- To review critical Src signaling pathways in osteoclasts and osteoblasts.
- To detail the structure-based design and screening of Src inhibitors for bone disease therapeutics.
Main Methods:
- Analysis of structural studies of Src and related kinases in various protein states.
- Design and synthesis of potent Src inhibitors based on identified binding site interactions.
- Evaluation of inhibitor potency using enzymatic/binding assays and efficacy in animal models of bone disease.
Main Results:
- Advances in structural biology have revealed key interactions for Src kinase inhibition.
- Novel Src inhibitors have been developed with nanomolar potency.
- These lead compounds demonstrate efficacy in preclinical animal models of bone disease.
Conclusions:
- Src tyrosine kinase is a validated therapeutic target for bone diseases.
- Structure-based drug design has yielded potent Src inhibitors.
- These inhibitors represent promising candidates for developing new treatments for bone disorders.