A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt

Elucidation of an Allosteric Mode of Action for a Thienopyrazole RORγt Inverse Agonist

“…Recently, allosteric modulation of RORγt was shown to be a promising approach for drug development, featuring examples of allosteric ligands with high NR subtype selectivity and absence of competition with the endogenous ligands . The first example to emerge was the indazole MRL‐871 (Figure ), a potent inverse agonist.…”

RORγ Structural Plasticity and Druggability

“…Compounds 1 -8 were cocrystallized with the LBD [11,[38][39][40][41]. Compound 9 was modeled from MD simulations [42]. The eight co-crystal structures overlap with the backbone RMSDs < 1.5 Å, supporting the same conformation of the AF-2 allosteric pocket that occurs in all the structures.…”

“…What is more, H11' is more accessible for a ligand sitting in this pocket than the orthosteric one. H11' is another unique feature only existing in the ROR family and is not conserved between RORα, RORβ, and RORγ [22,42]. Targeting the residues in H11' provides opportunities for increased drug selectivity.…”

“…The corresponding PDB codes for the co-crystal models of the compounds binding in the RORγ LBD are listed as follows:(1) 4YPQ, 5C4O[11]; (2) 5C4S[11]; (3) 5C4U[11]; (4) 5C4T[11]; (5) 6UCG[38]; (6) 6TLM[39]; (7) 5LWP[40]; (8) 6SAL[41]. No PDB code is available for compound 9[42].…”

RORγ Structural Plasticity and Druggability

“…Compounds 1-8 were co-crystallized with the LBD [11,[37][38][39][40]. Compound 9 was modeled from MD simulations [41]. The eight co-crystal structures overlap with the backbone RMSDs <1.5 Å, supporting the same conformation of the AF-2 allosteric pocket that occurs in all the structures.…”