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Article Dans Une Revue Journal of Medicinal Chemistry Année : 2015

Identification of noncompetitive inhibitors of cytosolic 5′-nucleotidase II using a fragment-based approach

Résumé

We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.
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Dates et versions

hal-01251800 , version 1 (06-01-2016)

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Zsuzsanna Marton, Rémi Guillon, Isabelle Krimm, Rahila Rahimova, David Egron, et al.. Identification of noncompetitive inhibitors of cytosolic 5′-nucleotidase II using a fragment-based approach. Journal of Medicinal Chemistry, 2015, 58 (24), pp.9680-9696. ⟨10.1021/acs.jmedchem.5b01616⟩. ⟨hal-01251800⟩
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