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Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate

Synthesis and Activity of a Novel Autotaxin Inhibitor-Icodextrin Conjugate

Natalie Fisher, Michael G Edwards, Ryan Hemming, Steven M Allin, John D Wallis, Philip C Bulman Page, Michael J Mckenzie, Stefanie M Jones, Mark R J Elsegood, John King-Underwood, Alan Richardson

J Med Chem. 2018 Sep 13;61(17):7942-7951.

PMID: 30059212

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1312201005	HA155		1312201-00-5	Price

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