Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil™) and potential of other CXCR4 antagonists as stem cell mobilizers.
AMD3100 was originally discovered as an anti-HIV agent effective in inhibiting the replication of HIV in vitro at nanomolar concentrations. We found it to be a potent and selective antagonist of CXCR4, the receptor for the chemokine SDF-1 (now called CXCL12). AMD3100 was then developed, and marketed, as a stem cell mobilizer, and renamed plerixafor (Mozobil™). The path to the discovery of Mozobil™ as a stem cell mobilizer was described in Biochem. Pharmacol. 77: 1655-1664 (2009). Here I review the recent advances that have consolidated the role of plerixafor in mobilizing hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) from the bone marrow into the blood circulation. Plerixafor acts synergistically with granulocyte colony-stimulating factor (G-CSF), and its usefulness has been proven particularly for the mobilization of HSCs and HPCs for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). Plerixafor also has great potential for the treatment of hematological malignancies other than NHL and MM, and non-hematological malignancies, and, eventually, several other diseases depending on the CXCL12-CXCR4 interaction. Various AMD3100 analogs have been described (i.e. AMD11070, AMD3465, KRH-3955, T-140, and 4F-benzoyl-TN14003), primarily as potential anti-HIV agents. They are all strong CXCR4 antagonists. Their role in stem cell mobilization remains to be assessed.
De Clercq
Erik
E
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. erik.declercq@rega.kuleuven.be
D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins
D019380:Anti-HIV Agents; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor