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PDBsum entry 5cf8
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Transferase/transferase inhibitor
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PDB id
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5cf8
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Crystal structure of janus kinase 2 in complex with n,n-dicyclopropyl- 10-ethyl-7-[(3-methoxypropyl)amino] -3-methyl-3,5,8,10- tetraazatricyclo[7.3.0.0,6] dodeca-1(9),2(6),4,7,11-pentaene-11- carboxamide
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Structure:
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Tyrosine-protein kinase jak2. Chain: a, b. Fragment: catalytic domain, unp residues 839-1132. 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: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.80Å
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R-factor:
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0.191
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R-free:
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0.204
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Authors:
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J.S.Sack
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Key ref:
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H.Wan
et al.
(2015).
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.
Acs Med Chem Lett,
6,
850-855.
PubMed id:
DOI:
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Date:
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08-Jul-15
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Release date:
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26-Aug-15
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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.
287 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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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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Acs Med Chem Lett
6:850-855
(2015)
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PubMed id:
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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.
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H.Wan,
G.M.Schroeder,
A.C.Hart,
J.Inghrim,
J.Grebinski,
J.S.Tokarski,
M.V.Lorenzi,
D.You,
T.Mcdevitt,
B.Penhallow,
R.Vuppugalla,
Y.Zhang,
X.Gu,
R.Iyer,
L.J.Lombardo,
G.L.Trainor,
S.Ruepp,
J.Lippy,
Y.Blat,
J.S.Sack,
J.A.Khan,
K.Stefanski,
B.Sleczka,
A.Mathur,
J.H.Sun,
M.K.Wong,
D.R.Wu,
P.Li,
A.Gupta,
P.N.Arunachalam,
B.Pragalathan,
S.Narayanan,
N.K C,
P.Kuppusamy,
A.V.Purandare.
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ABSTRACT
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JAK2 kinase inhibitors are a promising new class of agents for the treatment of
myeloproliferative neoplasms and have potential for the treatment of other
diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME
guided refinement of C-4 heterocycles to address metabolic liability present in
dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11),
with excellent kinome selectivity, in vivo PD activity, and safety profile.
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