title: Chemical genetics screening reveals KIAA1363 as a cytokine-lowering target.
abstract: Inflammation is a hallmark of many human diseases, including pain, arthritis, atherosclerosis, obesity and diabetes, cancer, and neurodegenerative diseases. Although there are several successfully marketed small molecules anti-inflammatory drugs such as cyclooxygenase inhibitors and glucocorticoids, many of these compounds are also associated with various adverse cardiovascular or immunosuppressive side effects. Thus, identifying novel anti-inflammatory small molecules and their targets is critical for developing safer and more effective next-generation treatment strategies for inflammatory diseases. Here, we have conducted a chemical genetics screen to identify small molecules that suppress the release of the inflammatory cytokine TNFα from stimulated macrophages. We have used an enzyme class-directed chemical library for our screening efforts to facilitate subsequent target identification using activity-based protein profiling (ABPP). Using this strategy, we have found that KIAA1363 is a novel target for lowering key pro-inflammatory cytokines through affecting key ether lipid metabolism pathways. Our study highlights the application of combining chemical genetics with chemoproteomic and metabolomic approaches toward identifying and characterizing anti-inflammatory smal molecules and their targets.
authors.affiliation: Program in Metabolic Biology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Devon M
authors.initials: DM
authors.lastname: Hunerdosse
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morris
authors.forename: David K
authors.initials: DK
authors.lastname: Miyamoto
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Fisher
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bateman
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Ghazaleh
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhong
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005786:Gene Expression Regulation; D057166:High-Throughput Screening Assays; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D054852:Small Molecule Libraries; D002265:Carboxylic Ester Hydrolases; C514712:Nceh1 protein, mouse; C515677:NCEH1 protein, human; D002787:Sterol Esterase