Retinoic acid receptor-related orphan
receptor γ
(RORγ)
acts as a crucial transcription factor in Th17 cells and is involved
in diverse autoimmune disorders. RORγ allosteric inhibitors
have gained significant research focus as a novel strategy to inhibit
RORγ transcriptional activity. Leveraging the high affinity
and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and
characterization of 11 allosteric fluorescent probes. Utilizing the
preferred probe 12h, we established an efficient and
cost-effective fluorescence polarization-based affinity assay for
screening RORγ allosteric binders. By employing virtual screening
in conjunction with this assay, 10 novel RORγ allosteric inhibitors
were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate
that probe 12h possesses the potential to function as
a powerful tool in facilitating the exploration of RORγ allosteric
inhibitors and furthering understanding of RORγ function.