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

• Published in: Journal of medicinal chemistry Vol. 58; no. 24; pp. 9680 - 9696
• Main Authors: Marton, Zsuzsanna, Guillon, Rémi, Krimm, Isabelle, Preeti, Rahimova, Rahila, Egron, David, Jordheim, Lars P, Aghajari, Nushin, Dumontet, Charles, Périgaud, Christian, Lionne, Corinne, Peyrottes, Suzanne, Chaloin, Laurent
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2015; Amer Chemical Soc
• Subjects: 5'-Nucleotidase - antagonists & inhibitors; Analytical chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Binding Sites; Biochemistry; Biochemistry, Molecular Biology; Cell Line, Tumor; Chemical Sciences; Chemistry, Medicinal; Computer Simulation; Databases, Chemical; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences; Life Sciences & Biomedicine; Medicinal Chemistry; Molecular Docking Simulation; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Pharmacology & Pharmacy; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Structure-Activity Relationship; PURPLE ACID-PHOSPHATASE; RECOGNITION; CN-II; DRUG DESIGN; RESISTANCE; ARYL; ACUTE MYELOID-LEUKEMIA; IMIDAZOLES; MUTATIONS; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01616

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.