Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12)
Autor: | Benjamin F. Cravatt, Jonathan J. Hulce, Daisuke Ogasawara, Taka-Aki Ichu, Alex Reed, Olesya A. Ulanovskaya, Hui Jing |
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Rok vydání: | 2019 |
Předmět: |
Cell Survival
Pyridines THP-1 Cells 01 natural sciences Article Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Piperidines In vivo Drug Discovery Genetic model Hydrolase Animals Humans Structure–activity relationship Enzyme Inhibitors 030304 developmental biology chemistry.chemical_classification 0303 health sciences Molecular Structure Chemistry Thiourea respiratory system Monoacylglycerol Lipases In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Biochemistry Lysophosphatidylserine Drug Design Lysophosphatidylinositol Cytokines Molecular Medicine lipids (amino acids peptides and proteins) |
Zdroj: | Journal of Medicinal Chemistry. 62:1643-1656 |
ISSN: | 1520-4804 0022-2623 |
Popis: | ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lyso-phosphatidylserine (lyso-PS) and lyso-phosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP)-guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo-active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways. |
Databáze: | OpenAIRE |
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