8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Authors: Paoletti, Julie; Assairi, Liliane; Gelin, Muriel; Huteau, Valerie; Nahori, Marie -Anne; Dussurget, Olivier; Labesse, Gilles; Pochet, Sylvie
Increased resistance of pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials. Biosynthetic pathways of several cofactors important for bacterial growth, such as nicotinamide adenine dinucleotide phosphate (NADP), have been proposed as a promising source of antibiotic targets. Nicotinamide adenine dinucleotide kinases (NADK; EC 18.104.22.168) are attractive for inhibitor development, since they catalyze the phosphorylation of NAD to NADP, which is an essential step of NADP metabolism. We previously synthesized diadenosine derivatives that inhibited NADK from two human pathogens, Listeria monocytogenes and Staphylococcus aureus, in the micromolar range. They behave as NAD mimics with the 5',5'-diphosphate group substituted by a 8,5' thioglycolic bridge. In an attempt to improve inhibitory potency, we designed new NAD mimics based on a single adenosine moiety harboring a larger derivatization attached to the C8 position and a small group at the 5' position. Here we report the synthesis of a series of 8-thioalkyl-adenosine derivatives containing various aryl and heteroaryl moieties and their evaluation as inhibitors of L. monocytogenes NADK1, S. aureus NADK and their human counterpart. Novel, sub-micromolar inhibitors of LmNADK1 were identified. Surprisingly, most LmNADK1 inhibitors demonstrated a high selectivity index against the close staphylococcal ortholog and the human NADK. Structural characterization of enzyme-inhibitor complexes revealed the original binding mode of these novel NAD mimics. (C) 2016 Elsevier Masson SAS. All rights reserved.
Discovering gene expression signatures responding to tyrosine kinase inhibitor treatment in chronic myeloid leukemia
BMC MEDICAL GENOMICS
Authors: Cha, Kihoon; Li, Yi; Yi, Gwan-Su
Background: Tyrosine kinase inhibitor (TKI)-based therapy is a recommended treatment for patients with chronic myeloid leukemia (CML). However, a considerable group of CML patients do not respond well to the TKI therapy. Challenging to overcome this problem, we tried to discover molecular signatures in gene expression profiles to discriminate the responders and non-responders of TKI therapy. Methods: We collected three microarray datasets of CML patients having total 73 responders and 38 non-responders. Statistical analysis was performed to identify differentially expressed genes (DEGs) as gene signature candidates from integrated microarray datasets. The classification performance of these genes and further selected discriminator gene sets was tested by using random forest and iterative backward variable selection methods. Results: We identified a set of genes including CTBP2, NADK, AZU1, CTSH, FSTL1, and HDLBP showing the highest accuracy more than 69.44 % to classify TKI response in CML patients. Interestingly, four genes of them are on the signaling pathway of cell proliferation. This set of genes showed much higher performance than the average performance of other genes in downstream signaling of TKI target, BCR-ABL. Conclusions: In this study, we could find a set of potential companion diagnostic markers for TKI treatment and, at the same time, the potential of gene expression analysis to enhance the coverage of companion diagnostics.