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

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Item Type:	Article
Title:	Pharmacological characterisation of a clinical candidate, TG-0054, a small molecule inverse agonist targeting CXCR4
Creators Name:	Pan, K.S., Wang, Z., Pfeil, C., Bergkamp, N.D., Mobach, S., Roth, S., Rizk, A., Lohse, M.J., Annibale, P., Siderius, M., Zimmermann, M., Smit, M.J. and Bosma, R.
Abstract:	CXCR4 is an important therapeutic target for haematopoietic stem cell mobilisation, which enhances the success of autologous stem cell transplantation for treating blood cancers such as lymphomas and myeloma. As CXCR4 has been shown to be involved in various inflammatory diseases, cancer progression and cell entry by the human immunodeficiency virus, understanding the molecular mechanism of CXCR4 inhibitors has potential implications in a wide area of diseases. Here we present an exploratory study which involves the molecular pharmacological characterisation of TG-0054 (Burixafor, GPC-100), a clinical candidate for HSC mobilisation. TG-0054 inhibited CXCL12 binding at CXCR4, and antagonises both Gαi and β-arrestin2 recruitment as well as the downstream Gαi-attenuation of cAMP signalling pathway, with pIC50 of 7.7, 8.0, and 7.9, respectively. Compared to the clinically used antagonist AMD3100 and the prototypical inverse agonist IT1t, TG-0054 displayed a unique pharmacological profile. Like IT1t, TG-0054 inhibited the constitutive Gαi signalling of CXCR4. However, in contrast to IT1t and other reported inverse agonists, TG-0054 was not able to induce monomerisation of CXCR4 oligomeric complexes. Considering the unique properties of TG-0054 on CXCR4, TG-0054 is an interesting tool compound for studying the relevance of inverse agonism as well as CXCR4 monomerisation in various pathologies.
Keywords:	Chemokine Receptors, G Protein-Coupled Receptors (GPCRs), Signal Transduction, CAMP
Source:	Molecular Pharmacology
ISSN:	0026-895X
Publisher:	American Society for Pharmacology and Experimental Therapeutics
Page Range:	100015
Number of Pages:	1
Date:	31 January 2025
Official Publication:	https://doi.org/10.1016/j.molpha.2025.100015
PubMed:	View item in PubMed

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