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PDBsum entry 5x1v
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References listed in PDB file
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Key reference
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Title
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Discovery and structure-Guided fragment-Linking of 4-(2,3-Dichlorobenzoyl)-1-Methyl-Pyrrole-2-Carboxamide as a pyruvate kinase m2 activator.
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Authors
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Y.Matsui,
I.Yasumatsu,
T.Asahi,
T.Kitamura,
K.Kanai,
O.Ubukata,
H.Hayasaka,
S.Takaishi,
H.Hanzawa,
S.Katakura.
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Ref.
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Bioorg Med Chem, 2017,
25,
3540-3546.
[DOI no: ]
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PubMed id
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Abstract
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Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the
pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic
intermediates as building blocks for biosynthetic processes, and thereby
supporting cell proliferation. Activation of PKM2 should invert aerobic
glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has
gained attention as a promising cancer therapy target. To obtain novel PKM2
activators, we conducted a high-throughput screening (HTS). Among several hit
compounds, a fragment-like hit compound with low potency but high ligand
efficiency was identified. Two molecules of the hit compound bound at one
activator binding site, and the molecules were linked based on the crystal
structure. Since this linkage succeeded in maintaining the original position of
the hit compound, the obtained compound exhibited highly improved potency in an
in vitro assay. The linked compound also showed PKM2 activating activity in a
cell based assay, and cellular growth inhibition of the A549 cancer cell line.
Discovery of this novel scaffold and binding mode of the linked compound
provides a valuable platform for the structure-guided design of PKM2 activators.
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