Discovery of a novel SHIP1 agonist that promotes degradation of lipid-laden phagocytic cargo by microglia

• DOI: 10.1016/j.isci.2022.104170
• Publication Date: 2022-03-26T22:18:24Z
• Authors: Chiara Pedicone; Sandra Fernandes; Alessandro Matera; Shea T. Meyer; Stewart Loh; Jeung-Hoi Ha; Denzil Bernard; John D. Chisholm; Rosa Chiara Paoli...; William G. Kerr
• Keywords: 0301 basic medicine; 03 medical and health sciences; Article

Here, we describe the use of artificial intelligence to identify novel agonists SH2-containing 5' inositol phosphatase 1 (SHIP1). One compounds, K306, represents most potent agonist identified date. We find that K306 exhibits selectivity for SHIP1 vs. paralog enzyme SHIP2, and this activation does not require C2 domain which other known require. Thus, a new class with mode agonism. Importantly, can suppress induction inflammatory cytokines iNOS in macrophages or microglia, but by their SHIP1-deficient counterparts. also reduces TNF-α production vivo an LPS-induced endotoxemia assay. Finally, show enhances phagolysosomal degradation synaptosomes dead neurons microglia revealing function might be exploited therapeutically dementia.