Discovery of novel N-sulfonamide-tetrahydroisoquinolines as potent retinoic acid receptor-related orphan receptor γt agonists.

Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small molecule immuno-oncology agents, including retinoic acid-related orphan receptor gamma t (RORγt), chemokine receptor, stimulator of interferon genes (Sting), indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR), etc. Among them, the retinoic acid receptor-related orphan receptor γt (RORγt) has gradually attracted more attention in these years. In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study. In this work, starting from compound 7 , compound 28 was obtained after 4 rounds of compound design, synthesis and SAR studies, which had an EC 50 of 0.021 ± 0.002 μM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC 50 of 0.021 ± 0.002 μM in mouse Th17 cell differentiation assay. It indicated that compound 28 had excellent RORγt agonistic activity and was expected to be developed as a new type of small molecule drug for cancer immunotherapy. The molecular dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramolecular interaction to stabilize H12, which helped RORγt to form the protein-binding site and therefore made the receptor ready to recruit coactivator. When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt. [Display omitted] • A series of Novel N-sulfonamide-tetrahydroisoquinolines Potent RORγt Agonists were discovered. • 28 possesses an EC 50 of 0.021 μM in dual-FRET assay and an EC 50 of 0.21 μM in mouse Th17 cell differentiation assay. • The triplet HYF in RORγt and the rigidity in 28 and s27 was the structural determinant for the functional switch of RORγt. [ABSTRACT FROM AUTHOR]