title: A reversed sulfonamide series of selective RORc inverse agonists.
abstract: The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom. Electronic address: Bodil.vanniel@crl.com.
authors.forename: Monique B
authors.initials: MB
authors.lastname: van Niel
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cartwright
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Gaines
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Killen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: René
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Ward
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: de Leon Boenig
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Everett
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Gancia
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Arunima
authors.initials: A
authors.lastname: Ganguli
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gobbi
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Lockey
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Maxine
authors.initials: M
authors.lastname: Norman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Qin
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wakes
authors.affiliation: Argenta, Early Discovery, Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000096:biosynthesis; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D016207:Cytokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013449:Sulfonamides
keywords: IL-17; Inflammation; RORc; RORγ; RORγt; X-ray structure