What question did this study set out to answer?

To identify and characterize an orally bioavailable inhibitor of cFMS receptor kinase to evaluate the role of CSF-1 signaling in normal physiology and disease states.

October 25, 2005Proceedings of the National Academy of SciencesOpen Access

Inhibition of colony-stimulating-factor-1 signalingin vivowith the orally bioavailable cFMS kinase inhibitor GW2580

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Authors

JCJames G. ConwayUniversity of North Carolina at Chapel Hill BMBrad McDonaldResearch Triangle Park Foundation JPJanet H. ParhamResearch Triangle Park Foundation

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Implication

Preclinical evaluation demonstrates selective CSF-1 receptor inhibition and suppressed bone degradation in rodent models, indicating potential utility against kinase-driven diseases.

Key Points

To identify and characterize an orally bioavailable inhibitor of cFMS receptor kinase to evaluate the role of CSF-1 signaling in normal physiology and disease states.
Tested GW2580 selectivity against human cFMS and 26 other kinases, evaluating cell proliferation and bone degradation in human osteoclast and rat bone cultures.
Administered oral GW2580 in mice to evaluate lipopolysaccharide-induced cytokine responses, peritoneal macrophage recruitment, and CSF-1-dependent tumor growth.
GW2580 completely inhibited human cFMS kinase in vitro at 0.06 µM while remaining inactive across 26 other kinases, and completely blocked CSF-1-induced monocyte growth and bone degradation at 1 µM.
Oral dosing in mice blocked exogenous CSF-1-driven IL-6 increases, reduced thioglycolate-induced peritoneal macrophage accumulation, and inhibited peritoneal M-NFS-60 tumor growth.
In vivo GW2580 treatment suppressed LPS-induced TNF production in mice, contrasting with its lack of effect on isolated monocytes and macrophages in vitro.

Cite This Study

Conway et al. (2005) studied this question.

synapsesocial.com/papers/69da21bc0f778bd2e468425c https://doi.org/10.1073/pnas.0502000102

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Implication

Preclinical evaluation demonstrates selective CSF-1 receptor inhibition and suppressed bone degradation in rodent models, indicating potential utility against kinase-driven diseases.

Inhibition of colony-stimulating-factor-1 signalingin vivowith the orally bioavailable cFMS kinase inhibitor GW2580

Discussion

Member takes

Implication

Key Points

Cite This Study

Inhibition of colony-stimulating-factor-1 signalingin vivowith the orally bioavailable cFMS kinase inhibitor GW2580

Discussion

Member takes

Implication

Key Points

Cite This Study

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