On October 15, 2021, Ma, Xiaojun; Sun, Nannan; Li, Xinwei; Fu, Wei published an article.Recommanded Product: 2567-29-5 The title of the article was Discovery of novel N-sulfonamide-tetrahydroisoquinolines as potent retinoic acid receptor-related orphan receptor γt agonists. And the article contained the following:
Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small mol. immuno-oncol. 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 mol. RORγt agonist developed by Lycera, has entered the phase II clin. 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 EC50 of 0.021 ± 0.002 μM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC50 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 mol. drug for cancer immunotherapy. The mol. dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramol. 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 mol. 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. The experimental process involved the reaction of 4-(Bromomethyl)-1,1′-biphenyl(cas: 2567-29-5).Recommanded Product: 2567-29-5
The Article related to sulfonamide tetrahydroisoquinoline potent retinoic acid receptor, agonists, cancer immunotherapy, inverse agonists, rorγt, Placeholder for records without volume info and other aspects.Recommanded Product: 2567-29-5
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