Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors

Abstract

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency

“…The latter can be classified in four distinct types depending on their binding modes to the tripartite site (19) (Fig.1C). The work on type III and type IV inhibitors has highlighted further the tunnel as a novel allosteric site to modulate ATX activity.…”

Lysophosphatidic acid produced by Autotaxin acts as an allosteric modulator of its catalytic efficiency

“…1A, B) has created a remarkable potential for selective inhibitor design 15,19,20 that includes lipid-based inhibitors 21 , DNA aptamers 22 and small molecules. The latter can be classified in four distinct types depending on their binding modes to the tripartite site 23 (Fig. 1C).…”

Identifying Novel ATX Inhibitors via Combinatory Virtual Screening Using Crystallography-Derived Pharmacophore Modelling, Docking Study, and QSAR Analysis

“…Recently, lots of patents and literature reported numerous ATX inhibitors with probable application for the treatment of diverse pathologies [10,14,[20][21][22]. For example, Nicolas Desroy identified a first-in-class ATX inhibitor, GLPG1690, which has been undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis [14].…”

“…An aminopyrimidine series with an ATX IC 50 of 500 nM were developed by Spencer B. Jones, for the treatment of osteoarthritis pain [10]. The imidazo [1,2-a]pyridine series of ATX inhibitors were identified by the Nicolas Desroy and Bertrand Heckmann group [22]. According to the different binding modes of a variety of endogenous ATX ligands and synthetic ATX inhibitors to the active site of the ATX protein, the Nicolas Desroy and Bertrand Heckmann group classified the diverse structural inhibitors into four types, illustrated in Figure 1 [22].…”

“…The imidazo [1,2-a]pyridine series of ATX inhibitors were identified by the Nicolas Desroy and Bertrand Heckmann group [22]. According to the different binding modes of a variety of endogenous ATX ligands and synthetic ATX inhibitors to the active site of the ATX protein, the Nicolas Desroy and Bertrand Heckmann group classified the diverse structural inhibitors into four types, illustrated in Figure 1 [22]. Type I inhibitors mimic the binding mode of LPC substrate and occupy the catalytic site, as shown in Figure 1A.…”