GLPG1690

Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode

Autotaxin, often abbreviated as ATX, is an enzyme that circulates in the body and is critically involved in the generation of lysophosphatidic acid, commonly known as LPA, which acts as a signaling molecule in various biological processes. The ATX/LPA signaling pathway has been implicated in the development and progression of a number of diseases, including fibrotic conditions, characterized by the excessive formation of scar tissue, and various forms of cancer.

Inhibitors of the ATX enzyme have been classified into five distinct types, based on the specific regions of the ATX protein they target. The ATX protein possesses a tripartite binding site, which includes the active site where the enzymatic reaction occurs, a hydrophobic pocket, and a tunnel that connects to the active site. The classification of ATX inhibitors (types I through V) reflects which of these components of the tripartite site are targeted by the inhibitor molecule.

In this research effort, the scientists aimed to explore a novel, “penultimate” type of inhibitor. This new class of inhibitors was designed with the goal of simultaneously targeting all three components of the ATX tripartite site: the active site, the pocket, and the tunnel. To achieve this, the researchers designed new chemical analogs that were based on an existing type IV inhibitor, GLPG1690, by introducing extensions to an ethyl group present in its structure. This design strategy successfully yielded new molecules that exhibited potent inhibitory activity against ATX.

The binding mode of these newly designed compounds was confirmed through the use of co-crystal structures. These structures revealed that the most promising compounds were indeed capable of engaging the ATX protein in a “three-point lock” binding mode, effectively interacting with the active site, the hydrophobic pocket, and the tunnel concurrently.

The study identified two particularly potent “type VI” inhibitors, designated as compound 4 and compound 41. These novel inhibitors demonstrated a significantly enhanced inhibitory activity against ATX, showing approximately a 40-fold increase in potency compared to compound 3, which is a close analog belonging to the type IV inhibitor class. Further investigation revealed that the type VI inhibitors, compound 4 and compound 41, exhibited cellular and phenotypic activities that were similar to those observed with the type IV inhibitor GLPG1690.

The identification of this new three-point lock binding mode represents a significant advancement in the combinatorial puzzle of ATX inhibitor design. This discovery completes the set of explored binding strategies targeting different combinations of the tripartite site. The researchers concluded that the characterization of this new type VI inhibitor binding mode warrants further investigation to fully understand its potential therapeutic benefits in the context of diseases where ATX/LPA signaling plays a critical role.