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PDBsum entry 5tts
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Transferase/transferase inhibitor
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PDB id
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5tts
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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 of a janus kinase 3 (jak3) specific inhibitor 1-((2s,5r)-5-((7h-Pyrrolo[2,3-D]pyrimidin-4-Yl)amino)-2-Methylpiperidin-1-Yl)prop-2-En-1-One (pf-06651600) allowing for the interrogation of jak3 signaling in humans.
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Authors
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A.Thorarensen,
M.E.Dowty,
M.E.Banker,
B.Juba,
J.Jussif,
T.Lin,
F.Vincent,
R.M.Czerwinski,
A.Casimiro-Garcia,
R.Unwalla,
J.I.Trujillo,
S.Liang,
P.Balbo,
Y.Che,
A.M.Gilbert,
M.F.Brown,
M.Hayward,
J.Montgomery,
L.Leung,
X.Yang,
S.Soucy,
M.Hegen,
J.Coe,
J.Langille,
F.Vajdos,
J.Chrencik,
J.B.Telliez.
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Ref.
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J Med Chem, 2017,
60,
1971-1993.
[DOI no: ]
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PubMed id
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Abstract
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Significant work has been dedicated to the discovery of JAK kinase inhibitors
resulting in several compounds entering clinical development and two FDA
approved NMEs. However, despite significant effort during the past 2 decades,
identification of highly selective JAK3 inhibitors has eluded the scientific
community. A significant effort within our research organization has resulted in
the identification of the first orally active JAK3 specific inhibitor, which
achieves JAK isoform specificity through covalent interaction with a unique JAK3
residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme
presented a unique challenge in the design of covalent inhibitors with
appropriate pharmacodynamics properties coupled with limited unwanted off-target
reactivity. This effort resulted in the identification of 11 (PF-06651600), a
potent and low clearance compound with demonstrated in vivo efficacy. The
favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to
its evaluation in several human clinical studies.
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