A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs

Huber M, Toy L, Schmidt M, Vogt H, Budzinski J, Wiefhoff MFJ, Merten N, Kostenis E, Weikert D, Schiedel M (2022)

Publication Type: Journal article

Publication year: 2022

Journal

DOI: 10.1002/anie.202116782

Abstract

A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled receptors (GPCRs). Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology toolbox targeting the IABS of CCR9. We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET as well as fluorescence microscopy. Applying this molecular tool in a membrane-based setup and in living cells, we discovered a 4-aminopyrimidine analogue as a new intracellular CCR9 antagonist with improved affinity. To chemically induce CCR9 degradation, we then developed the first PROTAC targeting the IABS of GPCRs. In a proof-of-principle study, we succeeded in showing that our CCR9-PROTAC is able to reduce CCR9 levels, thereby offering an unprecedented approach to modulate GPCR activity.

Authors with CRIS profile

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE)

How to cite

APA:

Huber, M., Toy, L., Schmidt, M., Vogt, H., Budzinski, J., Wiefhoff, M.F.J.,... Schiedel, M. (2022). A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.202116782

MLA:

Huber, Max, et al. "A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs." Angewandte Chemie International Edition (2022).

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