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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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References listed in PDB file
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Key reference
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Title
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Design, Synthesis and biological evaluation of novel fgfr inhibitors bearing an indazole scaffold.
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Authors
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J.Liu,
X.Peng,
Y.Dai,
W.Zhang,
S.Ren,
J.Ai,
M.Geng,
Y.Li.
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Ref.
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Org Biomol Chem, 2015,
13,
7643-7654.
[DOI no: ]
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PubMed id
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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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