| Literature DB >> 27879053 |
Christelle Doebelin1, Rémi Patouret1, Ruben D Garcia-Ordonez1, Mi Ra Chang1, Venkatasubramanian Dharmarajan1, Dana S Kuruvilla1, Scott J Novick1, Li Lin1, Michael D Cameron1, Patrick R Griffin1, Theodore M Kamenecka1.
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 (TH 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 TH 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.Entities:
Keywords: N-arylsulfonyl indolines; RORγ agonists; cancer immunotherapy; nuclear receptors
Mesh：
Substances：
Year: 2016 PMID： 27879053 PMCID： PMC5158182 DOI： 10.1002/cmdc.201600491
Source DB: PubMed Journal: ChemMedChem ISSN： 1860-7179 Impact factor: 3.466