In vitro characterization of compounds 1, 2, and 3 in Gal4-ROR hybrid reporter gene assays confirmed inverse RORγ agonism with micromolar to sub-micromolar IC50 values (Table ). The top-ranking compound 1 counteracted RORγ activity with an IC50 value of 4.6 µM. It was additionally active on RORα and RORβ, but precise IC50 values could not be determined due to cytotoxicity. Compounds 2 and 3 counteracted RORγ activity with IC50 values of 0.37 µM (2) and 0.68 µM (3), respectively. In addition to being inverse RORγ agonists, all three synthesized designs revealed pronounced preference for the RORγ subtype, with compounds 2 and 3 possessing more than tenfold higher potency on RORγ compared to the related RORα and RORβ isoforms. These results show that the CLM with beam search sampling conserved the bioactivity of the training molecules in the computational designs.