Download MendeleyIdentification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.
Marton, Z., Guillon, R., Krimm, I., Rahimova, R., Egron, D., Jordheim, L.P., Aghajari, N., Dumontet, C., Perigaud, C., Lionne, C., Peyrottes, S., Chaloin, L.(2015) J Med Chem 58: 9680-9696
- PubMed: 26599519
- DOI: https://doi.org/10.1021/acs.jmedchem.5b01616
- Primary Citation of Related Structures:
5CQZ, 5CR7 - PubMed Abstract:
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.
Organizational Affiliation:
Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), FRE 3689 CNRS, Université de Montpellier , 1919 route de Mende, 34293 Montpellier cedex 5, France.
