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Synthesis and activity of a novel Autotaxin inhibitor-Icodextrin conjugate
journal contributionposted on 2018-10-09, 10:22 authored by Natalie Fisher, Michael G. Edwards, Ryan Hemming, Steven M. Allin, John D. Wallis, Philip C. Bulman Page, Michael J. McKenzie, Stefanie M. Jones, Mark ElsegoodMark Elsegood, John King-Underwood, Alan Richardson
© Copyright 2018 American Chemical Society. Autotaxin is an extracellular phospholipase D that catalyses the hydrolysis of lysophosphatidyl choline (LPC) to generate the bioactive lipid lysophosphatidic acid (LPA). Autotaxin has been implicated in many pathological processes relevant to cancer. Intraperitoneal administration of an autotaxin inhibitor may benefit patients with ovarian cancer, however low molecular mass compounds are known to be rapidly cleared from the peritoneal cavity. Icodextrin is a polymer that is already in clinical use because it is slowly eliminated from the peritoneal cavity. Herein we report conjugation of the autotaxin inhibitor HA-155 to icodextrin. The conjugate inhibits autotaxin activity (IC50 = 0.86 ± 0.13 μg mL-1) and reduces cell migration. Conjugation of the inhibitor increased its solubility, decreased its membrane permeability and improved its intraperitoneal retention in mice. These observations demonstrate the first application of icodextrin as a covalently-bonded drug delivery platform with potential use in the treatment of ovarian cancer.
This research was supported by MRC (grant G1100184).
Published inJournal of Medicinal Chemistry
Pages7942 - 7951 (10)
CitationFISHER, N. ... et al., 2018. Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate. Journal of Medicinal Chemistry, 61, pp. 7942-7951.
Publisher© American Chemical Society (ACS)
- AM (Accepted Manuscript)
Publisher statementThis work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/
NotesThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00935.