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PDBsum entry 3mb7
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References listed in PDB file
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Key reference
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Title
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New potent dual inhibitors of ck2 and pim kinases: discovery and structural insights.
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Authors
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M.López-Ramos,
R.Prudent,
V.Moucadel,
C.F.Sautel,
C.Barette,
L.Lafanechère,
L.Mouawad,
D.Grierson,
F.Schmidt,
J.C.Florent,
P.Filippakopoulos,
A.N.Bullock,
S.Knapp,
J.B.Reiser,
C.Cochet.
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Ref.
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Faseb J, 2010,
24,
3171-3185.
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PubMed id
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Abstract
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Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence
of implication in growth dysregulation and apoptosis resistance, making it a
relevant target for cancer therapy. Several CK2 inhibitors have been developed
showing variable efficiency, emphasizing the need to expand the chemical
diversity of those inhibitors. We report the identification and characterization
of 2,8-difurandicarboxylic acid derivatives as a new class of nanomolar
ATP-competitive inhibitors. Selectivity profiling pointed out proviral insertion
Moloney virus kinases (Pim kinases) as the only other kinases that are
significantly inhibited. By combining structure-activity relationship analysis
with structural determination, we were able to determine the binding mode of
these inhibitors for both kinases and to explain their strong inhibitory
potency. Essential chemical features necessary for activity on both kinases were
then identified. The described compounds are not cell permeable: however, they
could provide a lead for developing novel inhibitors usable also in vivo. Given
the similar but not redundant pathophysiological functions of CK2 and Pim family
members, such inhibitors would provide new attractive leads for targeted cancer
therapy. This work highlights that 2 functionally related kinases from different
kinome branches display exquisite sensitivity to a common inhibitor.-Ramos, M.
L., Prudent, R., Moucadel, V., Sautel, C., Barette, C., Lafanechère, L.,
Mouawad, L., Grierson, D., Schmidt, F., Florent, J.-C., Filippakopoulos, P.,
Bullock, A. N., Knapp, S., Reiser, J.-B., Cochet, C. New potent dual inhibitors
of CK2 and Pim kinases: discovery and structural insights.
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