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Structure-based Design of Novel Boronic Acid-Based Inhibitors of Autotaxin

Structure-based Design of Novel Boronic Acid-Based Inhibitors of Autotaxin

Harald M H G Albers, Loes J D Hendrickx, Rob J P van Tol, Jens Hausmann, Anastassis Perrakis, Huib Ovaa

J Med Chem. 2011 Jul 14;54(13):4619-26.

PMID: 21615078

Abstract:

Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in inflammation, fibrosis, and tumor progression, rendering ATX an attractive drug target. We recently described a boronic acid-based inhibitor of ATX, named HA155 (1). Here, we report the design of new inhibitors based on the crystal structure of ATX in complex with inhibitor 1. Furthermore, we describe the syntheses and activities of these new inhibitors, whose potencies can be explained by structural data. To understand the difference in activity between two different isomers with nanomolar potencies, we performed molecular docking experiments. Intriguingly, molecular docking suggested a remarkable binding pose for one of the isomers, which differs from the original binding pose of inhibitor 1 for ATX, opening further options for inhibitor design.

Chemicals Related in the Paper:

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

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