title: N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor γ (RORγ) Agonists.
abstract: The nuclear retinoic acid receptor-related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (TH17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N-arylsulfonyl indolines as RORγ agonists. Structure-activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) analysis of RORγ-ligand complexes help rationalize the observed results.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Doebelin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Patouret
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Garcia-Ordonez
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Dharmarajan
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Novick
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
mesh_terms: D001665:Binding Sites; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
chemical_list: D007211:Indoles; D020381:Interleukin-17; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma; C057812:indoline
keywords: N-arylsulfonyl indolines; RORγ agonists; cancer immunotherapy; nuclear receptors