Pyrrolone Derivatives As Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Sep 27

PMID 30256641

Citations 11

Authors

Natalia V Ortiz Zacarias

Jacobus P D van Veldhoven

Laura Portner

Eric van Spronsen

Salviana Ullo

Margo Veenhuizen

Wijnand J C van der Velden

Annelien J M Zweemer

Roy M Kreekel

Kenny Oenema

Eelke B Lenselink

Laura H Heitman

Adriaan P IJzerman

Affiliations

Soon will be listed here.

Abstract

The recent crystal structures of CC chemokine receptors 2 and 9 (CCR2 and CCR9) have provided structural evidence for an allosteric, intracellular binding site. The high conservation of residues involved in this site suggests its presence in most chemokine receptors, including the close homologue CCR1. By using [H]CCR2-RA-[ R], a high-affinity, CCR2 intracellular ligand, we report an intracellular binding site in CCR1, where this radioligand also binds with high affinity. In addition, we report the synthesis and biological characterization of a series of pyrrolone derivatives for CCR1 and CCR2, which allowed us to identify several high-affinity intracellular ligands, including selective and potential multitarget antagonists. Evaluation of selected compounds in a functional [S]GTPγS assay revealed that they act as inverse agonists in CCR1, providing a new manner of pharmacological modulation. Thus, this intracellular binding site enables the design of selective and multitarget inhibitors as a novel therapeutic approach.

Citing Articles

Inducing Receptor Degradation as a Novel Approach to Target CC Chemokine Receptor 2 (CCR2).

Ortiz Zacarias N, Roth S, Broekhuis J, van der Es D, Moreau K, Heitman L Int J Mol Sci. 2024; 25(16).

PMID: 39201670 PMC: 11354370. DOI: 10.3390/ijms25168984.

Synthesis and computational evaluation of the antioxidant activity of pyrrolo[2,3-]quinoxaline derivatives.

Nguyen N, Dai V, Mechler A, Meervelt L, Hoa N, Vo Q RSC Adv. 2024; 14(34):24438-24446.

PMID: 39108963 PMC: 11299642. DOI: 10.1039/d4ra03108c.

Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1.

Toy L, Huber M, Lee M, Bartolome A, Ortiz Zacarias N, Nasser S ACS Pharmacol Transl Sci. 2024; 7(7):2080-2092.

PMID: 39022357 PMC: 11249626. DOI: 10.1021/acsptsci.4c00182.

Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5.

Dawson J, Wadman G, Zhang P, Tebben A, Carter P, Gu S bioRxiv. 2023; .

PMID: 38014122 PMC: 10680698. DOI: 10.1101/2023.11.15.567150.

Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2.

Huber M, Wurnig S, Toy L, Weiler C, Merten N, Kostenis E J Med Chem. 2023; 66(14):9916-9933.

PMID: 37463496 PMC: 10388362. DOI: 10.1021/acs.jmedchem.3c00769.

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