Quinoline-Pyrazole Scaffold as a Novel Ligand of Galectin-3 and Suppressor of TREM2 Signaling

Moustafa Gabr; Ashfaq Ur Rehman; Hai-Feng Chen

doi:10.1021/acsmedchemlett.0c00330

Quinoline-Pyrazole Scaffold as a Novel Ligand of Galectin-3 and Suppressor of TREM2 Signaling

ACS Med Chem Lett. 2020 Aug 11;11(9):1759-1765. doi: 10.1021/acsmedchemlett.0c00330. eCollection 2020 Sep 10.

Authors

Moustafa Gabr¹, Ashfaq Ur Rehman^{2

3}, Hai-Feng Chen^{3

4}

Affiliations

¹ Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, United States.
² Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
³ State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
⁴ Shanghai Center for Bioinformation Technology, Shanghai 200235, China.

Abstract

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.