The invention provides an RORγ receptor agonist comprising a compound of formula (I), wherein the variables are as defined herein. These compounds are analogous to known RORγ receptor antagonists. The invention further provides a method of activating -the nuclear receptor RORγ, comprising -contacting the RORγ with an effective amount or concentration of a compound of the invention; and a method of treating cancer in a patient, comprising administering to the patient an effective dose of a compound of the invention.
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.
Doebelin, Christelle,Patouret, Rémi,Garcia-Ordonez, Ruben D.,Chang, Mi Ra,Dharmarajan, Venkatasubramanian,Kuruvilla, Dana S.,Novick, Scott J.,Lin, Li,Cameron, Michael D.,Griffin, Patrick R.,Kamenecka, Theodore M.
supporting information
p. 2607 - 2620
(2016/12/09)
Novel palladium-catalyzed atom-efficient cross-coupling reaction by means of hexaarylcyclotrisiloxane
Hexaarylcyclotrisiloxane, which is one of the most stable derivatives of diarylsilanediol, was found to undergo palladium-catalyzed cross-coupling reaction with aryl halides in good yields. The reaction is performed in an aqueous medium taking potassium hydroxide as an activator. Both of the two aryl groups attached to each silicon atom could be utilized. Some base-sensitive functionality such as acetyl and nitro groups survived the reaction. Georg Thieme Verlag Stuttgart.