title: Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo.
abstract: Retinoic acid receptor-related orphan nuclear receptor γ (RORγ) orchestrates a pro-inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where RORγ expression is induced under specific pro-inflammatory conditions, γδ T cells and other innate-like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre-existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ-dependent gene expression programme in both Th17 cells and RORγ-expressing γδ T cells as well as a disease-relevant subset of human RORγ-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte-driven mouse model of psoriasis.
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Daliya
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Palanichamy
authors.affiliation: Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA.
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Liaomin
authors.initials: L
authors.lastname: Peng
authors.affiliation: Translational Sciences - Pathology, Biogen, Cambridge, MA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Quigley
authors.affiliation: Translational Sciences - Pathology, Biogen, Cambridge, MA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hamann
authors.affiliation: Translational Sciences - Pathology, Biogen, Cambridge, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dunstan
authors.affiliation: Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cullen
authors.affiliation: Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA.
authors.forename: Norm
authors.initials: N
authors.lastname: Allaire
authors.affiliation: Medicinal Chemistry, Biogen, Cambridge, MA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guertin
authors.affiliation: Medicinal Chemistry, Biogen, Cambridge, MA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry, Biogen, Cambridge, MA, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Loh
authors.affiliation: Immunology Research, Biogen, Cambridge, MA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Fontenot
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003872:Dermatitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C000609642:BIO-0554019; D001549:Benzamides; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011725:Pyridines; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: ROR
  γ; T helper type 17; imiquimod; γδ T cells and autoimmunity