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PDBsum entry 4lts
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Transferase/transferase inhibitor
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PDB id
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4lts
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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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Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors
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Structure:
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Nicotinamide phosphoribosyltransferase. Chain: a, b. Synonym: namprtase, nampt, pre-b-cell colony-enhancing factor 1, pre- b cell-enhancing factor, visfatin. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: nampt, pbef, pbef1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.69Å
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R-factor:
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0.158
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R-free:
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0.190
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Authors:
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X.Zheng,T.Baumeister,A.J.Buckmelter,M.Caligiuri,K.H.Clodfelter,B.Han, Y.Ho,N.Kley,J.Lin,D.J.Reynoids,G.Sharma,C.C.Smith,Z.Wang, P.S.Dragovich,A.Oh,W.Wang,M.Zak,L.Wang,P.Yuen,K.W.Bair
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Key ref:
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X.Zheng
et al.
(2014).
Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Bioorg Med Chem Lett,
24,
337-343.
PubMed id:
DOI:
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Date:
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23-Jul-13
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Release date:
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25-Dec-13
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PROCHECK
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Headers
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References
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P43490
(NAMPT_HUMAN) -
Nicotinamide phosphoribosyltransferase from Homo sapiens
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Seq:
Struc:
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491 a.a.
472 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.2.4.2.12
- nicotinamide phosphoribosyltransferase.
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Reaction:
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beta-nicotinamide D-ribonucleotide + diphosphate = 5-phospho-alpha-D- ribose 1-diphosphate + nicotinamide + H+
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beta-nicotinamide D-ribonucleotide
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+
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diphosphate
Bound ligand (Het Group name = )
matches with 55.56% similarity
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=
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5-phospho-alpha-D- ribose 1-diphosphate
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+
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nicotinamide
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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
24:337-343
(2014)
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PubMed id:
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Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
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X.Zheng,
T.Baumeister,
A.J.Buckmelter,
M.Caligiuri,
K.H.Clodfelter,
B.Han,
Y.C.Ho,
N.Kley,
J.Lin,
D.J.Reynolds,
G.Sharma,
C.C.Smith,
Z.Wang,
P.S.Dragovich,
A.Oh,
W.Wang,
M.Zak,
Y.Wang,
P.W.Yuen,
K.W.Bair.
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ABSTRACT
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A co-crystal structure of amide-containing compound (4) in complex with the
nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling
were utilized to design and discover a potent novel cyanoguanidine-containing
inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell
proliferation IC50=9.7nM). Further SAR exploration identified several additional
cyanoguanidine-containing compounds with high potency and good microsomal
stability. Among these, compound 15 was selected for in vivo profiling and
demonstrated good oral exposure in mice. It also exhibited excellent in vivo
antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model.
The co-crystal structure of this compound in complex with the NAMPT protein was
also determined.
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