A High‐Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Martin Reynders - , Ludwig Maximilian University of Munich (Author)
  • Sabine Willems - , Ludwig Maximilian University of Munich (Author)
  • Julian A. Marschner - , Ludwig Maximilian University of Munich (Author)
  • Thomas Wein - , Ludwig Maximilian University of Munich (Author)
  • Daniel Merk - , Ludwig Maximilian University of Munich (Author)
  • Oliver Thorn-Seshold - , Chair of Organic Chemistry II (Author)

Abstract

Retinoic acid receptor-related orphan receptor γ (RORγ) is a nuclear hormone receptor with multiple biological functions in circadian clock regulation, inflammation, and immunity. Its cyclic temporal role in circadian rhythms, and cell-specific activity in the immune system, make it an intriguing target for spatially and temporally localised pharmacology. To create tools that can study RORγ biology with appropriate spatiotemporal resolution, we designed light-dependent inverse RORγ agonists by building azobenzene photoswitches into ligand consensus structures. Optimizations gave photoswitchable RORγ inhibitors combining a large degree of potency photocontrol, with remarkable on-target potency, and excellent selectivity over related off-target receptors. This still rare combination of performance features distinguishes them as high quality photopharmaceutical probes, which can now serve as high precision tools to study the spatial and dynamic intricacies of RORγ action in signaling and in inflammatory disorders.

Details

Original languageEnglish
Article numbere202410139
JournalAngewandte Chemie International Edition
Publication statusE-pub ahead of print - 9 Sept 2024
Peer-reviewedYes

External IDs

unpaywall 10.1002/anie.202410139
Scopus 85208180087

Keywords