Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate

Allin, SM; Wallis, JD; Bulman Page, PC; Mckenzie, MJ; Jones, SM; Elsegood, MRJ; King-Underwood, J; Richardson, A; Fisher, N; Edwards, MG; Hemming, R

doi:10.1021/acs.jmedchem.8b00935

Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate

Allin, SM; Wallis, JD; Bulman Page, PC; Mckenzie, MJ; Jones, SM; Elsegood, MRJ; King-Underwood, J; Richardson, A; Fisher, N; Edwards, MG; Hemming, R

Authors

SM Allin

JD Wallis

PC Bulman Page

MJ Mckenzie

SM Jones

MRJ Elsegood

J King-Underwood

Alan Richardson a.richardson1@keele.ac.uk

N Fisher

Michael Edwards m.g.edwards@keele.ac.uk

R Hemming

Abstract

Autotaxin is an extracellular phospholipase D that catalyzes 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 HA155 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.

Acceptance Date	Jun 12, 2018
Publication Date	Aug 15, 2018
Journal	Journal of Medicinal Chemistry
Print ISSN	0022-2623
Publisher	American Chemical Society
Pages	7942-7951
DOI	https://doi.org/10.1021/acs.jmedchem.8b00935
Publisher URL	http://doi.org/10.1021/acs.jmedchem.8b00935