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PDBsum entry 5aep
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PDB id:
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Transferase
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Title:
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Novel pyrrole carboxamide inhibitors of jak2 as potential treatment of myeloproliferative disorders
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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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1.95Å
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R-factor:
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0.173
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R-free:
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0.213
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Authors:
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G.Canevari,J.Bertrand,M.G.Brasca,M.Nesi,N.Amboldi,N.Avanzi,S.Bindi, D.Casero,M.Ciomei,N.Colombo,S.Cribioli,G.Fachin,E.R.Felder, A.Galvani,A.Isacchi,I.Motto,A.Panzeri,P.Gnocchi,D.Donati
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Key ref:
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M.G.Brasca
et al.
(2015).
Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.
Bioorg Med Chem Lett,
23,
2387-2407.
PubMed id:
DOI:
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Date:
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08-Jan-15
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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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O60674
(JAK2_HUMAN) -
Tyrosine-protein kinase JAK2 from Homo sapiens
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Seq:
Struc:
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1132 a.a.
289 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
23:2387-2407
(2015)
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PubMed id:
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Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.
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M.G.Brasca,
P.Gnocchi,
M.Nesi,
N.Amboldi,
N.Avanzi,
J.Bertrand,
S.Bindi,
G.Canevari,
D.Casero,
M.Ciomei,
N.Colombo,
S.Cribioli,
G.Fachin,
E.R.Felder,
A.Galvani,
A.Isacchi,
I.Motto,
A.Panzeri,
D.Donati.
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ABSTRACT
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Compound 1, a hit from the screening of our chemical collection displaying
activity against JAK2, was deconstructed for SAR analysis into three regions,
which were explored. A series of compounds was synthesized leading to the
identification of the potent and orally bioavailable JAK2 inhibitor 16
(NMS-P830), which showed an encouraging tumour growth inhibition in SET-2
xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated
by in vivo pharmacodynamic effects.
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Links
