Pyrimidine-based compounds modulate CXCR2-mediated signaling and receptor turnover
1Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
Molecular Pharmaceutics
|June 5, 2014
Summary
Researchers identified novel pyrimidine-based compounds that modulate chemokine receptor CXCR2 signaling. The lead compound, CX797, inhibits IL8-mediated signaling and cell migration, offering potential anti-inflammatory and anti-cancer therapeutics.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Chemokine receptor CXCR2 is crucial for neutrophil recruitment and angiogenesis in inflammation and cancer.
- CXCR2 and its ligands are upregulated in tumors, promoting growth, angiogenesis, and invasiveness.
- Despite research, no CXCR2 inhibitors are clinically approved for treating inflammatory diseases or cancer.
Purpose of the Study:
- To screen for novel CXCR2 modulators using a high-throughput, cell-based assay.
- To identify and characterize a new class of pyrimidine-based compounds targeting CXCR2.
- To investigate the mechanism of action of the lead compound, CX797, and compare it to existing inhibitors.
Main Methods:
- High-throughput screening of an in-house compound library using a CXCR2-specific cell-based assay.
- Assessing the effects of lead compounds on IL8-mediated signaling pathways, including cAMP and β-arrestin-2 recruitment.
- Evaluating the impact of CX797 on IL8-mediated cell migration.
- Mechanistic comparison of CX797 with a known CXCR2 inhibitor, SB265610.
Main Results:
- A novel class of pyrimidine-based compounds was identified that modulate CXCR2 signaling.
- The lead compound, CX797, inhibited IL8-mediated cAMP signaling and receptor degradation.
- CX797 specifically upregulated IL8-mediated β-arrestin-2 recruitment and inhibited IL8-mediated cell migration.
- CX797 demonstrated a distinct mechanism of action compared to the CXCR2 inhibitor SB265610.
Conclusions:
- Pyrimidine-based compounds represent a promising new class of CXCR2 modulators.
- CX797 exhibits potent inhibitory effects on CXCR2-mediated signaling and cell migration.
- These findings provide a foundation for developing novel therapeutics targeting CXCR2 for inflammatory diseases and cancer.
More Related Videos
07:41A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
8.4K
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
8.9K
Related Concept Videos
01:15Receptor Downregulation in MVBs
2.0K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.0K
01:12GPCR Desensitization
6.1K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
6.1K
01:22Amplifying Signals via Enzymatic Cascade
15.2K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
15.2K
01:09GPCRs Regulate Adenylyl Cylase Activity
6.8K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
6.8K
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
81
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
81