Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders

Abstract

Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations.

The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT

“…The pathogenic role of RORγT, which participates in the development of Th17 cells in the development of certain autoimmune diseases, has been recognized, and RORγT has become a potential target for therapy against these diseases. Thus, many researchers have focused on the search for substances with inverse agonist activity against RORγT [36]. Nevertheless, due to the ability of Th17 cells to increase the immune response, at least in some types of cancer [59], and their use in adoptive cell therapy [60,61,62], an increasing number of researchers have also recognized the therapeutic potential of RORγT agonists [35,37].…”

“…Due to the involvement of RORγ/RORγT in the development of the immune system, the regulation of metabolism, and the pathogenesis of autoimmune diseases and increasing evidence for their involvement in cancer biology, they have become the putative targets for drug design [34]. Indeed, an increasing number of articles have reported new compounds that modulate the activity of these receptors in agonistic [35] and inverse agonistic manners [36], with potential for use in adoptive cell therapy (ACT) or the treatment of select autoimmune diseases.…”

Transcriptional Regulators of T Helper 17 Cell Differentiation in Health and Autoimmune Diseases

“…Several molecules targeting RORγt have been discovered and tested in murine models: digoxin, urosolic acid, and SR1001 reduce EAE severity (83)(84)(85); BI119 abrogates experimental colitis (86); SR2211 and JNJ-54271074 have therapeutic effect on experimental arthritis (87,88); TMP778 and S18-000003 show efficacy in a psoriasis-like skin inflammation model (89,90). In addition, other RORγt inverse agonists have been discovered (carbazole carboxamides, MG2778, TAK-828F, 6-substituted quinolines, A213) and tested as negative regulators of Th17 response (Table 1) (91)(92)(93)(94)(95)(96).…”

Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis

“…Using a scaffold hybridization strategy, a series of carbazole carboxamides are found to be potent RORγt inverse agonists ( 81 ). In addition, MG 2778, a cyclopenta[a]phenanthrene derivative, is identified as a lead compound for developing synthetic steroidal inverse agonists of RORγt ( 82 ). Furthermore, TAK-828F, a potent and selective RORγt inverse agonist, strongly inhibits Tc17 and Th17 cell differentiation from naive T cells and memory CD4 + T cells without affecting Th1 cell differentiation ( 83 ).…”