Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

Abstract

CXCR4 antagonists (e.g., Plerixafor ) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell-based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4-binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer-aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long-term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

“…These mutations act as gain-of-function mutations that turn CXCR4 into a truncated receptor with impaired internalization/desensitization and amplified signaling properties that dramatically impact on its biological functions, resulting in a "high-performance" receptor associated with aberrant expression and activity, and with chemotherapy resistance in WM patients [7]. Since CXCR4 is an attractive target for diverse diseases and is considered as one of the best potential targets in hematological tumors, several efforts are currently ongoing aimed at developing specific inhibitors including small molecules, peptides, antibodies, and siRNA that abrogate receptor activity [8]. Of note, several clinical trials proposed CXCR4 inhibitors for treatment of hematological tumors alone or in combination with chemotherapy or biological agents [9].…”

WHIM syndrome: Immunopathogenesis, treatment and cure strategies

“…However, this type of treatment will need to be lifelong much like insulin therapy of type I diabetes. A large number of inhibitors are in development including small molecules, peptides, antibodies, and siRNA as CXCR4 is an attractive target for diverse diseases (see below) . The small molecule bicyclam plerixafor (Mozobil, AMD3100) marketed by Sanofi is a specific CXCR4 antagonist approved by the FDA in 2008 in combination with G‐CSF for hematopoietic stem cell mobilization and transplantation in patients receiving cytoreductive treatment for multiple myeloma or non‐Hodgkins lymphoma.…”

“…A large number of inhibitors are in development including small molecules, peptides, antibodies, and siRNA as CXCR4 is an attractive target for diverse diseases (see below). 67,68 The small molecule bicyclam plerixafor (Mozobil, AMD3100) marketed by Sanofi is a specific CXCR4 antagonist approved by the FDA in 2008 in combination with G-CSF for hematopoietic stem cell mobilization and transplantation in patients receiving cytoreductive treatment for multiple myeloma or non-Hodgkins lymphoma. Efforts to repurpose plerixafor in WHIM syndrome are underway, and to date in several small studies it has been demonstrated to reverse panleukopenia in WHIM patients.…”

A Kinetic Fluorescence-based Ca²⁺ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

“…CXCR4 is highly expressed in more than twenty types of human cancer and controls tumor cell survival, proliferation, and migration as well as tumor-related angiogenesis 10 . CXCR4 antagonists of different chemical classes have previously been described 11,12 , but only the small molecule AMD3100 is currently approved for use in the clinic as a stem cell mobilization agent used during treatment of lymphoma and myeloma patients 13,14 . Clinical trials are ongoing to evaluate the safety and efficacy of several other CXCR4 antagonists in different human diseases, but with a strong focus on oncology…”

“…Receptor antagonists preventing binding to the receptor and subsequent activation by the endogenous agonist (CXCL12) currently form the main category of compounds specifically targeting CXCR4 11,12 . AMD3100, the small molecule that was used to illustrate the performance of the Ca 2+ mobilization assay, is one of the most prominent examples of CXCR4 antagonists…”