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PDBsum entry 4p7e
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PDB id:
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Transferase
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Title:
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Triazolopyridine compounds as selective jak1 inhibitors: from hit identification to glpg0634
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Structure:
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Tyrosine-protein kinase jak2. Chain: a, b. Fragment: residues 840-1132. Synonym: janus kinase 2,jak-2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: jak2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.40Å
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R-factor:
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0.208
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R-free:
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0.267
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Authors:
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C.C.J.Menet,S.Fletcher,G.Van Lommen,R.Geney,J.Blanc,K.Smits, N.Jouannigot,E.M.Van Der Aar,P.Clement-Lacroix,L.Lepescheux, R.Galien,B.Vayssiere,L.Nelles,T.Christophe,R.Brys,M.Uhring, F.Ciesielski,L.Van Rompaey
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Key ref:
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C.J.Menet
et al.
(2014).
Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.
J Med Chem,
57,
9323-9342.
PubMed id:
DOI:
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Date:
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27-Mar-14
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Release date:
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19-Nov-14
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PROCHECK
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Headers
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References
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O60674
(JAK2_HUMAN) -
Tyrosine-protein kinase JAK2 from Homo sapiens
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Seq:
Struc:
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1132 a.a.
283 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
57:9323-9342
(2014)
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PubMed id:
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Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.
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C.J.Menet,
S.R.Fletcher,
G.Van Lommen,
R.Geney,
J.Blanc,
K.Smits,
N.Jouannigot,
P.Deprez,
E.M.van der Aar,
P.Clement-Lacroix,
L.Lepescheux,
R.Galien,
B.Vayssiere,
L.Nelles,
T.Christophe,
R.Brys,
M.Uhring,
F.Ciesielski,
L.Van Rompaey.
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ABSTRACT
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Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of
multiple cytokines important in cellular function. Blockade of the JAK-STAT
pathway with a small molecule has been shown to provide therapeutic
immunomodulation. Having identified JAK1 as a possible new target for arthritis
at Galapagos, the compound library was screened against JAK1, resulting in the
identification of a triazolopyridine-based series of inhibitors represented by
3. Optimization within this chemical series led to identification of GLPG0634
(65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development
for RA and phase 2A development for Crohn's disease (CD).
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