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PDBsum entry 4d0w
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PDB id:
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Transferase
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Title:
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Pyrrole-3-carboxamides as potent and selective jak2 inhibitors
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Structure:
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Tyrosine-protein kinase jak2. Chain: a. Fragment: kinase domain, residues 835-1132. Synonym: janus kinase 2, jak-2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.
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Resolution:
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1.77Å
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R-factor:
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0.175
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R-free:
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0.215
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Authors:
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J.Bertrand,G.Canevari,M.Fasolini,M.G.Brasca,M.Nesi,N.Avanzi, D.Ballinari,T.Bandiera,S.Bindi,D.Carenzi,D.Casero,L.Ceriani, M.Ciomei,A.Cirla,M.Colombo,S.Cribioli,C.Cristiani,F.Della Vedova, G.Fachin,E.R.Felder,A.Galvani,A.Isacchi,D.Mirizzi,I.Motto,A.Panzeri, E.Pesenti,P.Vianello,P.Gnocchi,D.Donati
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Key ref:
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M.G.Brasca
et al.
(2014).
Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.
Bioorg Med Chem Lett,
22,
4998-5012.
PubMed id:
DOI:
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Date:
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30-Apr-14
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Release date:
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23-Jul-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.
291 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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Bioorg Med Chem Lett
22:4998-5012
(2014)
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PubMed id:
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Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.
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M.G.Brasca,
M.Nesi,
N.Avanzi,
D.Ballinari,
T.Bandiera,
J.Bertrand,
S.Bindi,
G.Canevari,
D.Carenzi,
D.Casero,
L.Ceriani,
M.Ciomei,
A.Cirla,
M.Colombo,
S.Cribioli,
C.Cristiani,
F.Della Vedova,
G.Fachin,
M.Fasolini,
E.R.Felder,
A.Galvani,
A.Isacchi,
D.Mirizzi,
I.Motto,
A.Panzeri,
E.Pesenti,
P.Vianello,
P.Gnocchi,
D.Donati.
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ABSTRACT
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We report herein the discovery, structure guided design, synthesis and
biological evaluation of a novel class of JAK2 inhibitors. Optimization of the
series led to the identification of the potent and orally bioavailable JAK2
inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth
inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed
in vivo by typical modulation of known biomarkers, and with a favourable
pharmacokinetic and safety profile.
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