TY - JOUR
T1 - Pharmacological characterisation of a clinical candidate, TG-0054, a small molecule inverse agonist targeting CXCR4
AU - Pan, Kylie S.
AU - Wang, Ziming
AU - Pfeil, Cy
AU - Bergkamp, Nick D.
AU - Mobach, Simon
AU - Roth, Susanne
AU - Rizk, Aurélien
AU - Lohse, Martin j.
AU - Annibale, Paolo
AU - Siderius, Marco
AU - Zimmermann, Mirjam
AU - Smit, Martine j.
AU - Bosma, Reggie
N1 - Funding: This research was funded by a European Union’s Horizon2020 MSCA Program (Grant agreement 860229 [ONCORNET2.0]), and C.P. was funded under the same program [Grant agreement 101063969]. Finally, N.B. and S.M. were funded by the Netherlands Organization for Scientific Research (NWO) [Grant agreement 881 ENPPS.TA.019.003].
PY - 2025/4/1
Y1 - 2025/4/1
N2 - CXCR4 is an important therapeutic target for hematopoietic stem cell mobilization, 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 characterization of TG-0054 (burixafor, GPC-100), a clinical candidate for hematopoietic stem cell mobilization. TG-0054 inhibited CXCL12 binding at CXCR4, and antagonized both Gαi and β-arrestin2 recruitment as well as the downstream Gαi-attenuation of cAMP signaling pathway, with pIC50 of 7.7, 8.0, and 7.9, respectively. Compared with the clinically used antagonist AMD3100 and the prototypical inverse agonist Isothiourea-1t (IT1t), TG-0054 displayed a unique pharmacological profile. Like IT1t, TG-0054 inhibited the constitutive Gαi signaling of CXCR4. However, in contrast to IT1t and other reported inverse agonists, TG-0054 was not able to induce monomerization 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 monomerization in various pathologies.
AB - CXCR4 is an important therapeutic target for hematopoietic stem cell mobilization, 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 characterization of TG-0054 (burixafor, GPC-100), a clinical candidate for hematopoietic stem cell mobilization. TG-0054 inhibited CXCL12 binding at CXCR4, and antagonized both Gαi and β-arrestin2 recruitment as well as the downstream Gαi-attenuation of cAMP signaling pathway, with pIC50 of 7.7, 8.0, and 7.9, respectively. Compared with the clinically used antagonist AMD3100 and the prototypical inverse agonist Isothiourea-1t (IT1t), TG-0054 displayed a unique pharmacological profile. Like IT1t, TG-0054 inhibited the constitutive Gαi signaling of CXCR4. However, in contrast to IT1t and other reported inverse agonists, TG-0054 was not able to induce monomerization 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 monomerization in various pathologies.
KW - cAMP
KW - Chemokine receptors
KW - G protein-coupled receptors
KW - Signal transduction
KW - CXCR4
UR - https://www.scopus.com/pages/publications/105001173851
U2 - 10.1016/j.molpha.2025.100015
DO - 10.1016/j.molpha.2025.100015
M3 - Article
SN - 0026-895X
VL - 107
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 4
M1 - 100015
ER -