GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol.

Autor: Sukhtankar DD; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Fung JJ; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Kim MN; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Cayton T; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Chiou V; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Caculitan NG; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Zalicki P; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Kim S; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Jo Y; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Kim S; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Lee JM; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Choi J; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Mun S; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Chin A; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America., Jang Y; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Lee JY; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Kim G; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Kim EH; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Huh WK; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.; Institute of Microbiology, Seoul National University, Seoul, Republic of Korea., Jeong JY; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Seen DS; GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea., Cardarelli PM; GPCR Therapeutics USA, Inc., Redwood City, California, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Oct 25; Vol. 18 (10), pp. e0287863. Date of Electronic Publication: 2023 Oct 25 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0287863
Abstrakt: Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.
Competing Interests: DDS, TC, VC, NGC, YJ, SK, JML, JC, SM, AC, JYL, GK, JYJ, DSS, and PMC are current employees. JJF, MK, PZ, SJK, YDJ and EHK were previously employed by GPCR Therapeutics, Inc. DDS and WKH are co-founders of GPCR Therapeutics. DSS, JJF, NGC, EHK, PZ and PMC have a patent pending for uses of GPCR inhibitors. The commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2023 Sukhtankar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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