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Ubiquitylation and ubiquitylation-like protein conjugation mechanisms are essential to many cell-biological activities. Ubiquitin forms conjugates with target proteins via a threestep mechanism (1-3). First, ubiquitin is activated at its carboxyl-terminal glycine by the ubiquitin-activating (E1) 1 enzyme to form a conjugate through the active cysteine in the E1 enzyme via a thiol ester bond. Next, ubiquitin is transferred from the E1 enzyme to one of several ubiquitin-conjugating (E2) enzymes. In the last step, ubiquitin attaches to a lysine within a target protein via an isopeptide bond. This step is often catalyzed by a member of the ubiquitin protein ligase (E3 enzyme) family. With regard to other modifiers, Nedd8, SUMOs, Apg12p, and Apg8ps (Apg8p in yeast, and, MAP-LC3, GABARAP, and GATE-16 in mammals), each is modified by specific E1 and E2 enzymes, and conjugated with its target (4 -10). Of these modifiers, Apg12p and MAP-LC3 (Apg8p in yeast) cooperatively play an essential role in the dynamic membrane formation of the autophagosome during autophagy.

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)­butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.