Structure-based design of novel boronic acid-based inhibitors of autotaxin

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.

Scheme 1. Autotaxin (ATX) is Responsible for Hydrolyzing the Lipid Lysophosphatidylcholine (LPC) into Lysophosphatidic Acid (LPA) and Choline

Figure 1

ATX structure liganded with inhibitor 1 (PDB ID 2XRG). (A) Surface representation of ATX with inhibitor 1 (magenta). (B) Binding of inhibitor 1 to the threonine oxygen nucleophile and two zinc ions. (C) Visualizing the ether linker of inhibitor 1 bound to ATX. (D) Visualizing the degree of freedom for the thiazolidine-2,4-dione core of inhibitor 1 in the ATX binding site.

Scheme 2. Synthetic Route Towards Linker Modified Inhibitors

Scheme 3. Synthetic Routes Towards Core Modified Inhibitors

Figure 2

(A) Focus from inside the protein on the thiazolidine-2,4-dione core of inhibitor 1 bound to ATX. (B) Inhibitor 1 docked into the active site of ATX to validate our docking approach. (C) The three best docking poses for the Z-isomer of 28. (D) The three best docking poses for the E-isomer of 28. Docking poses were generated using the docking program Glide.