title: Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.
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.
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Olivier
authors: O
authors: René
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Benjamin P
authors: BP
authors: Fauber
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Gladys de Leon
authors: Gde L
authors: Boenig
authors: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors: Brenda
authors: B
authors: Burton
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Céline
authors: C
authors: Eidenschenk
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Christine
authors: C
authors: Everett
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Alberto
authors: A
authors: Gobbi
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Sarah G
authors: SG
authors: Hymowitz
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Adam R
authors: AR
authors: Johnson
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: James R
authors: JR
authors: Kiefer
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Marya
authors: M
authors: Liimatta
authors: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors: Peter
authors: P
authors: Lockey
authors: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, U.K.
authors: Maxine
authors: M
authors: Norman
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Wenjun
authors: W
authors: Ouyang
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Heidi A
authors: HA
authors: Wallweber
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors: Harvey
authors: H
authors: Wong
keywords: IL-17; PBMC; RORc; RORγ; TH17; agonist; inverse agonist