期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 6, 期 3, 页码 276-281出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml500420y
关键词
RORc; ROR gamma; T(H)17; IL-17; PBMC; agonist; inverse agonist
资金
- NSERC
- NRC
- Canadian Institutes of Health Research
- Province of Saskatchewan, Western Economic Diversification Canada
- University of Saskatchewan at beamline 5.0.2 of the Advanced Light Source
- NIH
- NIGMS
- Howard Hughes Medical Institute
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenyl-sulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.
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