CXCRs (CXC chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, named CXCR1 through CXCR7. Among them, CXCR4 is the receptor for a chemokine known as CXCL12 (or SDF-1). CXCR4 is one of several chemokine co-receptors that HIV can use to infect CD4+ T cells. Moreover, oral cancer cells that acquired an SDF-1/CXCR4 autocrine loop exhibited enhanced cell motility and contributed to lung metastasis. Besides, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomaldominant immunodeficiency primarily caused by gain-of-function variants in the CXCR4 gene. This disease typically results in truncation of the carboxyl terminus of CXCR4 leading to impaired leukocyte trafficking between bone marrow and blood.
Mavorixafor (also known as AMD-070) is a potent, selective and orally active CXCR4 antagonist.
The mechanism underlying its antagonistic action on CXCR4 involves the establishment of a hydrogen bond between Mavorixafor‘s benzimidazole and CXCR4’s Tyr45 residue. In experiments, Mavorixafor does not affect cell anchorage, but notably curbed anchorage-independent growth. However, it substantially impeded SDF-1/CXCR4-driven migration and invasion in B88-SDF-1 cells. This inhibition highlighted Mavorixafor’s potential in disrupting crucial pathways pivotal for cancer cell dissemination and invasion. In addition, through daily oral dosing in nude mice bearing B88-SDF-1 cells, a profound outcome emerged. The administration of Mavorixafor substantially deterred the occurrence of lung metastasis, showcasing a tangible suppression of cancer spread when confronting this aggressive cellular behavior. Importantly, Mavorixafor is FDA approved for WHIM syndrome. Mavorixafor increases absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). Thus, Mavorixafor has the potential for WHIM syndrome research.
In conclusion, Mavorixafor is a selective and orally active CXCR4 antagonist, has the potential for WHIM syndrome and cancer research.
References:
[1] Daisuke Uchida, et al. Oncol Rep. 2018 Jul;40(1):303-308.
[2] Raffaele Badolato, et al. Blood. 2024 Apr 21:blood.2023022658.