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N ‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists
Author(s) -
Doebelin Christelle,
Patouret Rémi,
GarciaOrdonez Ruben D.,
Chang Mi Ra,
Dharmarajan Venkatasubramanian,
Kuruvilla Dana S.,
Novick Scott J.,
Lin Li,
Cameron Michael D.,
Griffin Patrick R.,
Kamenecka Theodore M.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600491
Subject(s) - orphan receptor , rar related orphan receptor gamma , nuclear receptor , retinoic acid , chemistry , regulator , receptor , retinoic acid receptor , linker , pharmacology , cancer research , microbiology and biotechnology , biology , biochemistry , transcription factor , gene , computer science , operating system
The nuclear retinoic acid receptor‐related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (T H 17) 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 T H 17 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.