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PDBsum entry 4z16
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Transferase/transferase inhibitor
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PDB id
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4z16
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References listed in PDB file
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Key reference
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Title
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Development of selective covalent janus kinase 3 inhibitors.
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Authors
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L.Tan,
K.Akahane,
R.Mcnally,
K.M.Reyskens,
S.B.Ficarro,
S.Liu,
G.S.Herter-Sprie,
S.Koyama,
M.J.Pattison,
K.Labella,
L.Johannessen,
E.A.Akbay,
K.K.Wong,
D.A.Frank,
J.A.Marto,
T.A.Look,
J.S.Arthur,
M.J.Eck,
N.S.Gray.
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Ref.
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J Med Chem, 2015,
58,
6589-6606.
[DOI no: ]
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PubMed id
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Abstract
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The Janus kinases (JAKs) and their downstream effectors, signal transducer and
activator of transcription proteins (STATs), form a critical immune cell
signaling circuit, which is of fundamental importance in innate immunity,
inflammation, and hematopoiesis, and dysregulation is frequently observed in
immune disease and cancer. The high degree of structural conservation of the JAK
ATP binding pockets has posed a considerable challenge to medicinal chemists
seeking to develop highly selective inhibitors as pharmacological probes and as
clinical drugs. Here we report the discovery and optimization of 2,4-substituted
pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909)
residue in JAK3. Investigation of structure-activity relationship (SAR)
utilizing biochemical and transformed Ba/F3 cellular assays resulted in
identification of potent and selective inhibitors such as compounds 9 and 45. A
2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent
interaction. Compound 9 exhibited decent pharmacokinetic properties and is
suitable for use in vivo. These inhibitors provide a set of useful tools to
pharmacologically interrogate JAK3-dependent biology.
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