They identify a compound capable of modulating cell migration in autoimmune and tumor processes

Cell migration plays a fundamental role in a multitude of physiological and pathological processes. The mechanisms behind this movement of cells are controlled by chemokines, proteins involved in the correct functioning of our immune system and whose inhibition of the union with their receptors has been a traditional therapeutic target to treat autoimmune, inflammatory and metastasis diseases in tumor processes.

Now, a team of scientists from the National Center for Biotechnology (CNB), the Margarita Salas Biological Research Center (CIB), both dependent on the Higher Council for Scientific Research (CSIC) in Spain, and the University of Linköping in Sweden, has identified a compound, called AGR1.137, capable of specifically modulating cell migration dependent on the chemokine receptor CXCR4, which would allow treating pathologies in which these proteins and their receptors intervene with fewer harmful side effects.

Chemokines, through interaction with their receptors, which are found in the cell membrane and have a structure that crosses the membrane forming a kind of barrel, determine cell migration involved in metastatic processes and autoimmune diseases, among other pathologies. Its therapeutic potential has been of great interest to the pharmaceutical industry, which has developed molecules aimed at inhibiting the binding between the chemokine and its receptor. However, so far, there are only a few compounds approved for clinical use, and they also cause significant side effects by completely blocking the function of these mediators.

The results obtained by the research team, headed by Eva M. García Cuesta of the CNB, show that “the ability to selectively block only some of the multiple functions of chemokine receptors, those of interest, would allow us to avoid unwanted effects.” in cellular physiology, and would minimize the appearance of side effects,” details Mario Mellado, CNB researcher and co-author of the study. With this idea in mind, the team looked for a target on the receptor molecule that would not interfere with the binding to the chemokine to keep part of the cell signaling intact and, at the same time, block that related to cell migration.

To this end, the team focused on analyzing compounds that target the area located between the TMV and TMVI transmembrane regions of the chemokine CXCL12 receptor. Thanks to the collaboration with the CIB, the research staff had access to a library of small aromatic compounds that, a priori, could interact with the specific region of the receptor that interested them, without affecting the binding of the chemokine. Starting from an in silico analysis (modeling, simulation and visualization of biological processes) of thousands of compounds, they identified three compounds that, in vitro, prevented cell migration, but allowed the signaling cascades necessary to maintain other functions in the cell to be maintained. cell. Finally, using zebrafish as a model, they were also able to observe in vivo how one of these molecules, called AGR1.137, decreased tumor growth and metastasis, without altering the binding of the chemokine CXCL12 to the receptor and keeping other signaling pathways active. .

Three-dimensional model of the structure of the chemokine receptor CXCR4 with the interaction zone with the compound identified in orange. (Image: César Santiago)

“Although this chemical compound is still far from being commercialized, it is the first time that a compound that modulates receptor activity has been identified that stabilizes a conformation of the receptor associated with the cell’s ability to move down the gradient,” Mellado stands out. “We have defined a new therapeutic target that allows action in inflammatory and autoimmune diseases and in processes such as tumor metastasis. Given its characteristics, this compound potentially presents lower toxicity and side effects when compared to other inhibitors,” he concludes.

The study is titled “Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain.” And it has been published in the academic journal eLIFE. (Source: CNB/CSIC)