N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor?? (ROR?) Agonists.

ABSTRACT: The nuclear retinoic acid receptor-related orphan receptor?? (ROR?; NR1F3) is a key regulator of inflammatory gene programs involved in T?helper 17 (TH 17) cell proliferation. As such, synthetic small-molecule repressors (inverse agonists) targeting ROR? have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing TH 17 cell proliferation through activation (agonism) of ROR? may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N-arylsulfonyl indolines as ROR? 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 ROR?-ligand complexes help rationalize the observed results.

SUBMITTER: Doebelin C 

PROVIDER: S-EPMC5158182 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature