N-Arylsulfonyl Indolines as Retinoic Acid Receptor-Related Orphan Receptor γ (RORγ) Agonists

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. Pharmacology switches from inverse agonist to agonist: Immunotherapy is an exciting new approach in oncology. RORγ agonists have the potential to enhance immune responses through modulation of TH17 cell proliferation. Starting from an N‐arylsulfonamide indoline RORγ inverse agonist, we were able to identify the key area where small modifications lead to RORγ agonists. A binding mode hypothesis, supported by HDX‐MS analysis, is also proposed.