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PDBsum entry 4rfm
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Transferase/inhibitor
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PDB id
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4rfm
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PDB id:
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Transferase/inhibitor
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Title:
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Itk kinase domain in complex with compound 1 n-{1-[(1,1-dioxo-1-thian- 2-yl)(phenyl)methyl]-1h- pyrazol-4-yl}-5,5-difluoro-5a-methyl-1h,4h, 4ah,5h,5ah,6h-cyclopropa[f]indazole-3-carboxamide
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Structure:
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Tyrosine-protein kinase itk/tsk. Chain: a. Fragment: kinase domain (unp residues 357-620). Synonym: interleukin-2-inducible t-cell kinase, il-2-inducible t-cell kinase, kinase emt, t-cell-specific kinase, tyrosine-protein kinase lyk. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: itk, emt, lyk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.10Å
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R-factor:
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0.206
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R-free:
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0.264
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Authors:
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P.A.Mcewan,J.J.Barker,C.Eigenbrot
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Key ref:
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J.D.Burch
et al.
(2015).
Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.
J Med Chem,
58,
3806-3816.
PubMed id:
DOI:
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Date:
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26-Sep-14
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Release date:
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29-Apr-15
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PROCHECK
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Headers
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References
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Q08881
(ITK_HUMAN) -
Tyrosine-protein kinase ITK/TSK from Homo sapiens
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Seq:
Struc:
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620 a.a.
249 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 4 residue positions (black
crosses)
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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
58:3806-3816
(2015)
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PubMed id:
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Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.
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J.D.Burch,
K.Barrett,
Y.Chen,
J.DeVoss,
C.Eigenbrot,
R.Goldsmith,
M.H.Ismaili,
K.Lau,
Z.Lin,
D.F.Ortwine,
A.A.Zarrin,
P.A.McEwan,
J.J.Barker,
C.Ellebrandt,
D.Kordt,
D.B.Stein,
X.Wang,
Y.Chen,
B.Hu,
X.Xu,
P.W.Yuen,
Y.Zhang,
Z.Pei.
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ABSTRACT
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The medicinal chemistry community has directed considerable efforts toward the
discovery of selective inhibitors of interleukin-2 inducible T-cell kinase
(ITK), given its role in T-cell signaling downstream of the T-cell receptor
(TCR) and the implications of this target for inflammatory disorders such as
asthma. We have previously disclosed a structure- and property-guided lead
optimization effort which resulted in the discovery of a new series of
tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose
further optimization of this series that resulted in further potency
improvements, reduced off-target receptor binding liabilities, and reduced
cytotoxicity. Specifically, we have identified a correlation between the
basicity of solubilizing elements in the ITK inhibitors and off-target
antiproliferative effects, which was exploited to reduce cytotoxicity while
maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2
and IL-13 production in vivo following oral or intraperitoneal dosing in mice.
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