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

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.

SUBMITTER: Gabr M

PROVIDER: S-EPMC7488289 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Gabr Moustafa M Rehman Ashfaq Ur AU Chen Hai-Feng HF

ACS medicinal chemistry letters 20200811 9

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 opti ...[more]

PMID: 32944144

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