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PDBsum entry 4zsa
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Transferase/transferase inhibitor
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PDB id
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4zsa
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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 fgfr1 kinase domain in complex with 7n
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Structure:
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Fibroblast growth factor receptor 1. Chain: a, b. Fragment: unp residues 458-765. Synonym: fgfr-1,basic fibroblast growth factor receptor 1,bfgf-r-1, fms-like tyrosine kinase 2,flt-2,n-sam,proto-oncogenE C-fgr. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr1, bfgfr, cek, fgfbr, flg, flt2, hbgfr. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.00Å
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R-factor:
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0.206
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R-free:
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0.254
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Authors:
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Q.F.Liu,Y.C.Xu
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Key ref:
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J.Liu
et al.
(2015).
Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.
Org Biomol Chem,
13,
7643-7654.
PubMed id:
DOI:
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Date:
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13-May-15
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Release date:
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17-Jun-15
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PROCHECK
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Headers
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References
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P11362
(FGFR1_HUMAN) -
Fibroblast growth factor receptor 1 from Homo sapiens
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Seq:
Struc:
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822 a.a.
290 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 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor 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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Org Biomol Chem
13:7643-7654
(2015)
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PubMed id:
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Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.
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J.Liu,
X.Peng,
Y.Dai,
W.Zhang,
S.Ren,
J.Ai,
M.Geng,
Y.Li.
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ABSTRACT
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Fibroblast growth factor receptor (FGFR) is a potential target for cancer
therapy. Based on the structure of AZD4547 and NVPBGJ-398, we designed novel
1H-indazol-3-amine scaffold derivatives by utilizing scaffold hopping and
molecular hybridization strategies. Consequently, twenty-eight new compounds
were synthesized and evaluated for their inhibitory activity against FGFR1.
Compound 7n bearing a 6-(3-methoxyphenyl)-1H-indazol-3-amine scaffold was first
identified as a potent FGFR1 inhibitor, with good enzymatic inhibition (IC50 =
15.0 nM) and modest cellular inhibition (IC50 = 642.1 nM). The crystal structure
of 7n bound to FGFR1 was obtained, which might provide a new basis for potent
inhibitor design. Further structural optimization revealed that compound 7r
stood out as the most potent FGFR1 inhibitor with the best enzyme inhibitory
(IC50 = 2.9 nM) and cellular activity (IC50 = 40.5 nM).
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