5cqz

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Clinical and preclinical observations have lead to the hypothesis that 5'-nucleotidase cN-II could constitute a therapeutic target in oncology, either per se or to increase the activity of cytotoxic nucleoside analogs. To identify potential cN-II inhibitors, we performed in silico screening of freely available chemical databases, in vitro enzymatic assays with recombinant cN-II, soaking experiments with crystals of truncated cN-II as well as biological evaluation of selected compounds, alone or in combination with cytotoxic nucleoside analogs, on cancer cells. The top ranked compounds from virtual screening included an anthraquinone derivative (AdiS) that were shown to block the enzyme activity with a K(i) of 2.0mM. Soaking experiments performed with crystals of truncated cN-II allowed to obtain crystallographic data at a resolution of 2.9A and indicating interaction between AdiS and F354/I152 situated in the effector site 1 of cN-II. In addition, this compound exhibited different levels of cytotoxicity in vitro on several cancer cell lines and increased the induction of apoptosis in RL cells incubated with 0.5 or 1.5muM cladribine, 0.05muM clofarabine or 30muM fludarabine. Finally, AdiS showed synergy with cladribine and additivity with clofarabine. This study showed that virtual screening is a useful tool for the identification of potent cN-II inhibitors, and our biological results indicated interesting activity for one lead compound that can be further developed as therapeutics.
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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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Identification and characterization of inhibitors of cytoplasmic 5'-nucleotidase cN-II issued from virtual screening.,Jordheim LP, Marton Z, Rhimi M, Cros-Perrial E, Lionne C, Peyrottes S, Dumontet C, Aghajari N, Chaloin L Biochem Pharmacol. 2012 Dec 7. pii: S0006-2952(12)00765-4. doi:, 10.1016/j.bcp.2012.11.024. PMID:23220537<ref>PMID:23220537</ref>
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Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.,Marton Z, Guillon R, Krimm I, Preeti, Rahimova R, Egron D, Jordheim LP, Aghajari N, Dumontet C, Perigaud C, Lionne C, Peyrottes S, Chaloin L J Med Chem. 2015 Dec 24;58(24):9680-96. doi: 10.1021/acs.jmedchem.5b01616. Epub, 2015 Dec 7. PMID:26599519<ref>PMID:26599519</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 11:36, 30 December 2015

Human cytosolic 5'-nucleotidase II in complex with 3-(3-Imidazol-1-ylphenyl)-N-(9H-purin-6-yl)benzamide

5cqz, resolution 2.90Å

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