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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Published on: February 20, 2018

Pharmacological characterization of a clinical candidate, TG-0054, a small molecule inverse agonist targeting CXCR4

Kylie S Pan1, Ziming Wang2, Cy Pfeil3

  • 1InterAx Biotech AG, Villigen, Switzerland; Division of Medicinal Chemistry, Faculty of Sciences, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Molecular Pharmacology
|March 29, 2025
PubMed

Insights

TG-0054 (burixafor) is a novel CXCR4 antagonist with inverse agonistic properties. It offers a unique mechanism for hematopoietic stem cell mobilization and potential therapeutic applications in various diseases.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • CXCR4 is a key target for hematopoietic stem cell mobilization in blood cancers.
  • CXCR4 antagonists have implications in inflammatory diseases, cancer, and HIV entry.

Purpose of the Study:

  • To characterize the molecular pharmacology of TG-0054, a clinical candidate for stem cell mobilization.
  • To compare TG-0054's profile with existing CXCR4 antagonists.

Main Methods:

  • Molecular pharmacological characterization of TG-0054.
  • Assays for CXCL12 binding, Gαi and β-arrestin2 recruitment, and cAMP signaling.
  • Comparison with AMD3100 and Isothiourea-1t (IT1t).

Main Results:

  • TG-0054 inhibited CXCL12 binding and antagonized Gαi/β-arrestin2 recruitment (pIC50s 7.7-8.0).
  • TG-0054 exhibited inverse agonism, inhibiting constitutive Gαi signaling.
  • Unlike IT1t, TG-0054 did not induce CXCR4 monomerization.

Conclusions:

  • TG-0054 possesses a unique pharmacological profile as a non-monomerizing inverse agonist.
  • TG-0054 is a valuable tool for studying CXCR4 signaling and its role in disease.
Keywords:
CXCR4Chemokine receptorsG protein-coupled receptorsSignal transductioncAMP

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