Potential Clinical Applications of the CXCR4 Antagonist Bicyclam AMD3100

Abstract

The bicyclam AMD3100 (originally called JM3100), in which the two cyclam rings are tethered by an aromatic bridge, emanated from JM2763, where the two cyclam moieties are tethered by an aliphatic linker - JM2763 in turn originated from JM1657, where the cyclam rings are directly linked to one another via a C-C bridge, and which was identified as an impurity, showing anti-HIV activity, in a commercial cyclam preparation. AMD3100 proved very effective against HIV-1 and HIV-2, inhibiting virus replication within the nM range, without toxicity for the host cells at concentrations that were > 100,000-fold higher than those required to inhibit HIV replication. The anti-HIV activity of AMD3100 appeared to be confined to the T-lymphotropic (X4) HIV strains, i.e. those strains that use the CXCR4 receptor to enter their target cells, and AMD3100 as of today still stands as one of the most potent and selective CXCR4 antagonists ever discovered. Hence, AMD3100 was found to interfere with a number of (patho)physiological processes which depend on the interaction of CXCR4 with its natural ligand, stromal derived factor (SDF-1) and which play an important role in rheumatoid, allergic and malignant diseases. AMD3100 has been shown to mobilize CD34+ stem cells from the bone marrow into the bloodstream and has also been shown to augment migration of bone marrow-derived endothelial progenitor cells into sites of neovascularization after myocardial infarction. Currently, AMD3100 is actively pursued as a stem cell mobilizer for transplantation in patients with multiple myeloma and non-Hodgkin's lymphoma.

Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function

“…Specifically, CXCR4 is an important coreceptor with CD4 for the HIV-1 envelope gp120/gp41 complex (15). AMD3100, which was found safe in human phase I clinical trials (31), has been successfully used to block CXCR4-dependent HIV-1 entry and replication (16,32). Moreover, engagement of CXCR4 by HIV gp120 in T cells induces a hyporesponsive state attributable to cAMP-dependent PKA signaling, although this mechanism appears to be TLRindependent (33).…”

The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil)

“…As reviewed previously [11], AMD3100, akin to SDF-1, specifically blocks those (Ttropic) virus strains using CXCR4 as the co-receptor, whereas neither AMD3100 nor SDF-1 exhibit any activity against the M-tropic virus strains using CCR5 as the co-receptor (Table 1) [5]. Vice versa, RANTES (the natural ligand of CCR5) effectively inhibited the M-tropic R5 virus strains, while not being active against the T-tropic R4 virus strains.…”

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…Therefore, development of strategies aiming either to promote or inhibit SDF-1-driven signals should have tremendous therapeutic implications. Several CXCR4antagonists are currently being validated for clinical use [70,71]. Chronic treatment of AMD3100 efficiently blocks SDF-1-mediated vasculogenesis [20,21].…”