Agonist Lock Touched and Untouched Retinoic Acid Receptor-Related Orphan Receptor-γt (RORγt) Inverse Agonists: Classification Based on the Molecular Mechanisms of Action

Abstract

Retinoic acid receptor-related orphan receptorgamma-t (RORγt) is a potential drug target for autoimmune diseases with a clear biological mechanism in the Th17/IL-17 pathway. The "agonist lock", which is formed by residues His479-Tyr502-Phe506 in RORγt, makes H12 tightly contact H11 in a suitable conformation for coactivator binding and, thus, is related to RORγt transcriptional activation. The inverse agonism of RORγt is complex because not all RORγt inverse agonists directly break the agonist lock to interfere with coactivator recruitment and the transcription of RORγt. Here, we analyze the complex structures, binding modes, and biological activities of various RORγt inverse agonists and classify them as "agonist lock touched" and "agonist lock untouched" RORγt inverse agonists according to whether they infringe on the agonist lock directly or not. We aim at providing a comprehensive review and insights into drug discovery of RORγt inverse agonists.

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

“…The oxygen atoms of the tetrahydropyran ring can interact with the side chain Arg367 by forming hydrogen bonds. In addition, phenyl ethyl can make a close contact with Trp317 (3.2 Å), which leads to destabilization of helix 12 in the agonist position. , The benzene ring of the chromone ring can form CH−π interactions with Met365. In addition, cyclobutane and Cys320 could form a pseudo-hydrogen bond (3.6 Å).…”

“…The organic layer was purified by column chromatography (eluted with 10−33% EtOAc in petroleum ether) to give 38 (35 mg, yield: 17%) as a colorless amorphous solid. 1 7-Hydroxy-2,3-dihydro-1H-inden-1-one (40). Phenol (5.0 g, 53.1 mmol) and 3-chloropropanoyl chloride (6.7 g, 53.1 mmol) were heated up to 90 °C under a nitrogen atmosphere for 2 h and cooled down to 25 °C; then, AlCl 3 (7.1 g, 53.1 mmol) was added and heated up to 100 °C for 1 h and to 160 °C for 2 h. It was then cooled down to 25 °C, quenched by 2 mol/L HCl (50 mL), and extracted with DCM (30 mL × 2), and the organic layer was combined.…”

“…7-Hydroxy-1-oxo-2,3-dihydro-1H-indene-4-sulfonyl Chloride (41). Compound 41 was prepared in a manner similar to that of compound 3, using 7-hydroxy-2,3-dihydro-1H-inden-1-one (40) and sulfonyl chloride as a colorless solid crude (250 mg).…”

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01436. 1 H NMR, 13 C NMR, LC−MS/MS, and HPLC of compounds GSK2981278, a1−a13, b1−b8, c1−c13, and d1−d11; compounds 5, 8, 13,16,17,18,20,21,23,29,36,38,40,42…”

Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human RORγT Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity

“…Clinical studies with antibodies neutralizing interleukin 17 (e.g., ixekizumab, bimekizumab [40,41]) indicate that the use of the inverse agonists of RORγT that regulate the expression of IL17 [16] may also be effective or may increase the effectiveness of these antibody actions in combination therapy. To date, 17 compounds have entered clinical trials [42], and new drug candidates are being discovered. However, some of these trials have been halted due to the lack of satisfactory results, toxicity, and tumor induction [43]; thus, new compounds with more effective action are needed.…”