GPC-100 Is a Novel CXCR4 Inhibitor That Leads to Improved <i>in Vitro</i> Potency and <i>In Vivo</i> Efficacy in Stem Cell Mobilization When Combined with a Beta-Blocker

Fung, Juan José; Chiou, Valerie; Lee, Jaemin; Jang, Yongdae; Choi, Junho; Zalicki, P.; Cayton, T. E.; Chin, Ashley; Caculitan, Niña; Kim, SoHui; Lee, Jiyeong; Sukhtankar, Devki; Kim, Eun‐Hee; Cardarelli, Josephine

doi:10.1182/blood-2022-160248

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“…In preclinical studies with mice, burixafor rapidly and effectively mobilized white blood cells (WBCs) as well as HSCs and progenitor cells into the circulation. This mobilization was statistically greater than that observed with plerixafor 3 …”

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confidence: 99%

“…All authors reviewed drafts of the manuscript, approved the final version, and agree to be accountable for the work. The results of this study were previously reported as an abstract and poster 3 …”

Section: Acknowledgmentsmentioning

confidence: 99%

“…Burixafor hydrobromide (also known as GPC-100 and TG-0054) is a potent antagonist of CXCR4 with a binding affinity (Ki) of 1.6 nM (1.2 ng/mL) Structure (Figure 1). 3 Burixafor blocks cellular migration in a number of CXCR4-expressing cells. Specifically, in a multiple myeloma cell line, MM.1S, burixafor was shown to inhibit CXCL12-induced migration with a half maximal inhibitory concentration IC50 of 20 nM (15.4 ng/mL) versus 80 nM (63.5 ng/mL) for plerixafor.…”

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confidence: 98%

“…This mobilization was statistically greater than that observed with plerixafor. 3 In preclinical studies, burixafor was not shown to be significantly metabolized in liver microsomes from human and other species. In addition, a mass spectrometry analysis for metabolites revealed that burixafor was the predominant component in these microsomes.…”

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Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC‐100), a Novel C‐X‐C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects

Sukhtankar

Chang

Tsai

et al. 2023

Clinical Pharm in Drug Dev

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Adequate mobilization of hematopoietic stem cells (HSCs), especially CD34+ cells, is necessary for stem cell transplantation in patients with hematological malignancies or autoimmune diseases. Burixafor is an inhibitor of the C‐X‐C Chemokine Receptor 4 that disrupts the C‐X‐C motif chemokine 12 (CXCL12)/CXCR4 axis in the bone marrow, releasing HSCs into circulation. In mice, a single intravenous dose of burixafor was rapidly absorbed (time to maximum concentration, 5 minutes) and increased peripheral white blood cell counts within 30 minutes. Additionally, burixafor was administered to 64 healthy subjects in a randomized, double‐blind, placebo‐controlled, single‐ascending‐dose study to evaluate safety, pharmacokinetics, and pharmacodynamics. Subjects received burixafor intravenous doses ranging from 0.10 to 4.40 mg/kg in 8 cohorts. Single doses were generally safe and well tolerated. Gastrointestinal events were reported at doses of 2.24 mg/kg or greater. Exposure (maximum concentration and area under the concentration–time curve) increased in an approximately dose‐proportional manner. Time to maximum concentration occurred with a median of 0.26–0.30 hours that was not dose proportional. As expected, white blood cell, CD133+ cell, and CD34+ cell concentrations generally increased with the increases in burixafor dose from 0.10 to 3.14 mg/kg. At maximal levels, the CD34+ cell counts increased 3‐ to 14‐fold from baseline levels. These results provide support for continued clinical development of burixafor.

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