Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site

Femke A. Meijer, M.C.M. van den Oetelaar, R.G. Doveston, E.N.R. Sampers, Lucas Brunsveld (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The nuclear receptor RORγt is a key positive regulator in the differentiation and proliferation of T helper 17 (Th17) cells and the production of proinflammatory cytokines like IL-17a. Dysregulation of this pathway can result in the development of various autoimmune diseases, and inhibition of RORγt with small molecules thus holds great potential as a therapeutic strategy. RORγt has a unique allosteric ligand binding site in the ligand binding domain, which is distinct from the canonical, orthosteric binding site. Allosteric modulation of RORγt shows high potential, but the targeted discovery of novel allosteric ligands is highly challenging via currently available methods. Here, we introduce covalent, orthosteric chemical probes for RORγt that occlude the binding of canonical, orthosteric ligands but still allow allosteric ligand binding. Ultimately, these probes could be used to underpin screening approaches for the unambiguous and rapid identification of novel allosteric RORγt ligands.
Original languageEnglish
Pages (from-to)631-639
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume12
Issue number4
DOIs
Publication statusPublished - 8 Apr 2021

Keywords

  • Nuclear receptors
  • RORγt
  • allosteric modulators
  • covalent probes

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