Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration

Abstract

AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34+stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin’s Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…Plerixafor was originally modeled after a predecessor called JM1657, which had been identified as an impurity in a commercial (mono)cyclam preparation intended as an anti-HIV agents and which selectively blocked the CXCR4 receptor. [162]. Other specific CXCR4/CXCL12 antagonists have been developed and are in different phases of clinical development.…”

“…CXCR4 is ubiquitously expressed in healthy normal cells; thus, CXCR4 signaling can produce several side effects due to the interference with immunological and physiological responses. Nevertheless, plerixafor and other CXCR4 antagonists [162] have shown minimal side effects in clinical studies. Small molecules and small peptides that target the CXCL12/CXCR4 axis pose several challenges in MM treatment.…”

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

“…To our knowledge, there are two chemokine receptor antagonists successfully applied in the clinic, but not in neuropathic pain treatment. These are maraviroc (CCR5 antagonist), an antiretroviral drug used against the human immunodeficiency virus, and plerixafor (CXCR4 antagonist) used in the treatment of non‐Hodgkin lymphoma and multiple myeloma . We believe that our tested antagonist of CCR1 may bring some beneficial properties in the treatment of neuropathic pain and will become a substance used in the clinic.…”

The Scope of Application of Macrocyclic Polyamines Beyond Metal Chelation

“…[67] MPAs have also been embedded as bioactive components per se, the most brilliant example being certainly AMD3100: [68] this bis-cyclam derivative is used as an antagonist of CXCR4 receptors, initially developed as an anti-HIV agent and subsequently repurposed for the mobilization of hematopoietic stem cells in cancer patients, now commercialized as Mozobil® (plerixafor). [69] AMD3100 was also studied for its ability to alter the copper metabolism in Alzheimer's disease (vide supra) [70] and as possible anti-malaria agent. [71] To improve the pharmacological properties of AMD3100, many derivatives have been designed and synthesized (Figure 9), in which the core structure of cyclam was changed for 1,4-dioxa-or 1,4-dithia-8,11-diazacyclotetradecane, [72] or for side-or cross-bridged cyclams [73] (also used for building original antimalarial agents) [74] thus expanding the chemistry of MPAs.…”