Structure-based design of a novel class of autotaxin inhibitors based on endogenous allosteric modulators

Clark, Jennifer M. and Salgado-Polo, Fernando and Macdonald, Simon J. F. and Barrett, Tim N. and Perrakis, Anastassis and Jamieson, Craig (2022) Structure-based design of a novel class of autotaxin inhibitors based on endogenous allosteric modulators. Journal of Medicinal Chemistry, 65 (8). 6338–6351. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.2c00368)

[thumbnail of Clark-etal-JMC-2022-Structure-based-design-of-a-novel-class-of-autotaxin-inhibitors]
Preview
 Text. Filename: Clark_etal_JMC_2022_Structure_based_design_of_a_novel_class_of_autotaxin_inhibitors.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo
Download (9MB)| Preview

Abstract

Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.

CORE (COnnecting REpositories)