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PDBsum entry 4hw7
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Transferase/transferase inhibitor
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PDB id
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4hw7
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References listed in PDB file
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Key reference
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Title
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Design and pharmacology of a highly specific dual fms and kit kinase inhibitor.
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Authors
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C.Zhang,
P.N.Ibrahim,
J.Zhang,
E.A.Burton,
G.Habets,
Y.Zhang,
B.Powell,
B.L.West,
B.Matusow,
G.Tsang,
R.Shellooe,
H.Carias,
H.Nguyen,
A.Marimuthu,
K.Y.Zhang,
A.Oh,
R.Bremer,
C.R.Hurt,
D.R.Artis,
G.Wu,
M.Nespi,
W.Spevak,
P.Lin,
K.Nolop,
P.Hirth,
G.H.Tesch,
G.Bollag.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
5689-5694.
[DOI no: ]
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PubMed id
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Abstract
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Inflammation and cancer, two therapeutic areas historically addressed by
separate drug discovery efforts, are now coupled in treatment approaches by a
growing understanding of the dynamic molecular dialogues between immune and
cancer cells. Agents that target specific compartments of the immune system,
therefore, not only bring new disease modifying modalities to inflammatory
diseases, but also offer a new avenue to cancer therapy by disrupting immune
components of the microenvironment that foster tumor growth, progression, immune
evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms)
oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene
homolog (KIT) are two hematopoietic cell surface receptors that regulate the
development and function of macrophages and mast cells, respectively. We
disclose a highly specific dual FMS and KIT kinase inhibitor developed from a
multifaceted chemical scaffold. As expected, this inhibitor blocks the
activation of macrophages, osteoclasts, and mast cells controlled by these two
receptors. More importantly, the dual FMS and KIT inhibition profile has
translated into a combination of benefits in preclinical disease models of
inflammation and cancer.
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