Open AccessQuinoline-Pyrazole Scaffold as a Novel Ligand of Galectin-3 and Suppressor of TREM2 Signaling
Author(s) -
Moustafa T. Gabr,
Ashfaq Ur Rehman,
Haifeng Chen
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00330
Subject(s) - trem2 , proinflammatory cytokine , galectin , neuroinflammation , ligand (biochemistry) , chemistry , suppressor , microbiology and biotechnology , galectin 1 , microglia , receptor , cancer research , biology , biochemistry , immunology , inflammation , myeloid cells , gene
Galectin-3 has been identified as a critical player in driving the neuroinflammatory responses in Alzheimer's disease (AD). A key feature of this function of galectin-3 is associated with its interaction with the triggering receptor expressed on myeloid cells-2 (TREM2). Herein, we report a high-throughput screening (HTS) platform that can be used for the identification of inhibitors of TREM2 and galectin-3 interaction. We have utilized this HTS assay to screen a focused library of compounds optimized for the central nervous system (CNS)-related diseases. MG-257 was identified from this screen as the first example of a small molecule that can attenuate TREM2 signaling based on its high affinity to galectin-3 (endogenous ligand of TREM2). Remarkably, MG-257 reduced the levels of proinflammatory cytokines in activated microglial cells, which highlights its ability to inhibit the neuroinflammatory response associated with AD.