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

Femke A Meijer; Maxime C M van den Oetelaar; Richard G Doveston; Ella N R Sampers; Luc Brunsveld

doi:10.1021/acsmedchemlett.1c00029

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

ACS Med Chem Lett. 2021 Mar 8;12(4):631-639. doi: 10.1021/acsmedchemlett.1c00029. eCollection 2021 Apr 8.

Authors

Femke A Meijer¹, Maxime C M van den Oetelaar¹, Richard G Doveston^{1

2}, Ella N R Sampers¹, Luc Brunsveld¹

Affiliations

¹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
² Leicester Institute of Structural and Chemical Biology and School of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.

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.