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PDBsum entry 5mql
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References listed in PDB file
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Key reference
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Title
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Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.
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Authors
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K.Hammam,
M.Saez-Ayala,
E.Rebuffet,
L.Gros,
S.Lopez,
B.Hajem,
M.Humbert,
E.Baudelet,
S.Audebert,
S.Betzi,
A.Lugari,
S.Combes,
S.Letard,
N.Casteran,
C.Mansfield,
A.Moussy,
P.De sepulveda,
X.Morelli,
P.Dubreuil.
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Ref.
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Nat Commun, 2017,
8,
1420.
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PubMed id
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Abstract
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Masitinib, a highly selective protein kinase inhibitor, can sensitise
gemcitabine-refractory cancer cell lines when used in combination with
gemcitabine. Here we report a reverse proteomic approach that identifies the
target responsible for this sensitisation: the deoxycytidine kinase (dCK).
Masitinib, as well as other protein kinase inhibitors, such as imatinib,
interact with dCK and provoke an unforeseen conformational-dependent activation
of this nucleoside kinase, modulating phosphorylation of nucleoside analogue
drugs. This phenomenon leads to an increase of prodrug phosphorylation of most
of the chemotherapeutic drugs activated by this nucleoside kinase. The
unforeseen dual activity of protein kinase inhibition/nucleoside kinase
activation could be of great therapeutic benefit, through either reducing
toxicity of therapeutic agents by maintaining effectiveness at lower doses or by
counteracting drug resistance initiated via down modulation of dCK target.
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