Choline Kinase—More Than a Cancer Therapy Target?

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Choline Kinase—More Than a Cancer Therapy Target?

RESEARCH HIGHLIGHTS Nature Reviews Rheumatology 10, 699 (2014); published online 21 October 2014; doi:10.1038/nrrheum.2014.180 RHEUMATOID ARTHRITIS Choline kinase—more than a cancer therapy target? “Blocking choline kinase suppressed the By immunohistochemistry, western blot Fibroblast-like synoviocyte in RA 1 aggressive behavior of fibroblast-like and H magnetic resonance spectroscopy, ATP + choline synoviocytes in rheumatoid arthritis the researchers showed choline kinase α Mg2+ Choline and was highly effective in a preclinical is highly expressed in the synovium of kinase model of arthritis,” says Monica Guma, patients with RA, particularly in the Phosphocholine + ADP corresponding author of a study published intimal layer, and also in ex vivo cultured in Annals of the Rheumatic Diseases. fibroblast-like synoviocytes. Expression NPG Phosphatidylcholine Choline kinase is a phosphotransferase of the enzyme was shown to be induced enzyme that catalyzes the conversion of by inflammatory stimuli, including TNF, In reference to ongoing and planned choline to phosphocholine, a first step in IL-1 and platelet-derived growth factor, work, the lead researcher of the study, the biosynthesis of phosphatidylcholine but not lipopolysaccharide. Gary Firestein, comments, “We would (see figure). Phosphatidylcholine The researchers found that mitogen- like to determine the suitability of choline metabolism affects cell proliferation, activated protein kinase and PI3K/Akt metabolites or other metabolites as migration and signalling, and through signalling by fibroblast-like synoviocytes biomarkers of fibroblast-like synoviocyte these mechanisms is thought to be an could be reduced with a choline activation and joint damage in patients important regulator of tumorigenesis. kinase inhibitor (MN58b). These data with RA. If successful, our studies could In explanation of why her group began complement knowledge of the tumour cell translate into important diagnostic and studying metabolic abnormalities in RA, biology and contribute to understanding prognostic tests.” Guma says, “Targeting the metabolome of the mouse modelling data, that is, Nicholas J. Bernard in cancer is now emerging as a potential administration of MN58b reduced clinical therapeutic approach. The joint in RA has scores of established disease severity in the many characteristics of tumors, including K/BxN serum transfer mouse model of Original article Guma, M. et al. Choline kinase inhibition hypoxia and high levels of oxygen radicals, inflammatory arthritis, when compared in rheumatoid arthritis. Ann. Rheum. Dis. doi:10.1136/ annrheumdis-2014-205696 nitric oxide and cytokines.” with vehicle-treated control mice. NATURE REVIEWS | RHEUMATOLOGY VOLUME 10 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved.

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Identification and Validation of Novel and More Effective Choline Kinase
www.nature.com/scientificreports OPEN Identifcation and validation of novel and more efective choline kinase inhibitors against Streptococcus pneumoniae Tahl Zimmerman1*, Valerie Chasten1, Juan Carlos Lacal2 & Salam A. Ibrahim1 Streptococcus pneumoniae choline kinase (sChoK) has previously been proposed as a drug target, yet the efectiveness of the frst and only known inhibitor of sChoK, HC-3, is in the millimolar range. The aim of this study was thus to further validate sChoK as a potential therapeutic target by discovering more powerful sChoK inhibitors. LDH/PK and colorimetric enzymatic assays revealed two promising sChoK inhibitor leads RSM-932A and MN58b that were discovered with IC50 of 0.5 and 150 μM, respectively, and were shown to be 2–4 magnitudes more potent than the previously discovered inhibitor HC-3. Culture assays showed that the minimum inhibitory concentration (MIC) of RSM- 932A and MN58b for S. pneumoniae was 0.4 μM and 10 μM, respectively, and the minimum lethal concentration (MLC) was 1.6 μM and 20 μM, respectively. Western blot monitoring of teichoic acid production revealed diferential patterns in response to each inhibitor. In addition, both inhibitors possessed a bacteriostatic mechanism of action, and neither interfered with the autolytic efects of vancomycin. Cells treated with MN58b but not RSM-932A were more sensitive to a phosphate induced autolysis with respect to the untreated cells. SEM studies revealed that MN58b distorted the cell wall, a result consistent with the apparent teichoic acid changes. Two novel and more highly potent putative inhibitors of sChoK, MN58b and RSM-932A, were characterized in this study.
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Table S1. List of Oligonucleotide Primers Used
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DATASHEET USA: [email protected]
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