叔磺酰胺RORc配体的微小结构变化导致相反的作用机制。
Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.
作者信息
René Olivier, Fauber Benjamin P, Boenig Gladys de Leon, Burton Brenda, Eidenschenk Céline, Everett Christine, Gobbi Alberto, Hymowitz Sarah G, Johnson Adam R, Kiefer James R, Liimatta Marya, Lockey Peter, Norman Maxine, Ouyang Wenjun, Wallweber Heidi A, Wong Harvey
机构信息
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
出版信息
ACS Med Chem Lett. 2014 Dec 4;6(3):276-81. doi: 10.1021/ml500420y. eCollection 2015 Mar 12.
Abstract
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 phenylsulfonamides 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.
摘要
叔磺酰胺类RORc配体的微小结构变化导致了不同的作用机制。两种化合物的共晶体结构揭示了机制上一致的蛋白质构象变化。优化后的苯磺酰胺被鉴定为RORc激动剂，而苄基磺酰胺则表现出强效的反向激动剂活性。在我们的生化分析中表现为激动剂的化合物也会导致人外周血单个核细胞中IL-17的产生增加，而反向激动剂在相同的分析条件下会导致IL-17的显著抑制。最有效的反向激动剂化合物对ROR异构体以及所有其他被分析的核受体表现出超过180倍的选择性。
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