Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.

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.

• Authors: Zsuzsanna Marton, Rémi Guillon, Isabelle Krimm, Preeti, Rahila Rahimova, David Egron, Lars P Jordheim, Nushin Aghajari, Charles Dumontet, Christian Périgaud, Corinne Lionne, Suzanne Peyrottes, Laurent Chaloin
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 24 Pg. 9680-96 (Dec 24 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26599519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Benzoates
• Imidazoles
• Naphthalenes
• Purines
• Pyrroles
• 5'-Nucleotidase
• NT5C2 protein, human

Topics

• 5'-Nucleotidase (antagonists & inhibitors)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzamides (chemical synthesis, chemistry, pharmacology)
• Benzoates (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Computer Simulation
• Databases, Chemical
• Drug Screening Assays, Antitumor
• Drug Synergism
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Molecular Docking Simulation
• Naphthalenes (chemical synthesis, chemistry, pharmacology)
• Purines (chemical synthesis, chemistry, pharmacology)
• Pyrroles (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship