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Synthesis and activity of a novel Autotaxin inhibitor-Icodextrin conjugate

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posted on 09.10.2018, 10:22 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.

Funding

This research was supported by MRC (grant G1100184).

History

School

  • Science

Department

  • Chemistry

Published in

Journal of Medicinal Chemistry

Volume

61

Pages

7942 - 7951 (10)

Citation

FISHER, 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)

Version

AM (Accepted Manuscript)

Publisher statement

This 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/

Acceptance date

30/07/2018

Publication date

2018-07-30

Notes

This 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.

ISSN

0022-2623

eISSN

1520-4804

Language

en

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