How was a stem cell mobilizer, which can be applied in the treatment of diseases such as Non-Hodgkin’s lymphoma, discovered? The demonstration of the stem cell mobilizing potential of AMD3100 (plerixafor, or Mozobil) was the result of a series of serendipitous discoveries. It all started with the unexpected finding that an impurity present in a (mono)cyclam preparation, a bicyclam, which is an organic compound, proved active in exhibiting anti-HIV activity. This activity could be ascribed to a totally unprecedented mode of action, tentatively ascribed to the interaction of the bicyclam with a yet-unknown process in the replicative cycle of HIV: viral uncoating. Viral uncoating is the process in which, upon penetrating the cell, the virus releases nucleic acid into the host. The impurity – bicyclam – interacted with the HIV viral uncoating, and worked against it.
The original article on these serendipitous discoveries was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), sponsored by the Nobel Prize winner, Max Perutz. Lead optimization of the original bicyclam led to the identification of a clinical candidate, AMD3100 (AMD standing for AnorMED, the company that originally developed the compound as a potential anti-HIV drug).
In the initial preliminary clinical trials, carried out at Johns Hopkins, it appeared that AMD3100 caused an increase in the white blood cell counts, rather than a decrease as should be expected for toxic compounds. This increased number of white blood cells appeared, at closer inspection, to carry the CD34+ marker, characteristic for hematopoietic stem cells, which are immature cells that can develop into all types of blood cells, including white and red blood cells. Thus the concept was born that AMD3100 was, in fact, a stem cell mobilizer, thus justifying its trade name as “Mozobil”.
Mozobil was quickly approved as a stem cell mobilizer to be used in the autologous bone marrow transplantation of hematopoietic stem cells in some malignant diseases such as Non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Yet, the potential use of AMD3100 (plerixafor) reaches much further than NHL and MM, as it may be useful in stem cell mobilization and in application in many other conditions where the use of stem cells could be beneficial.
Erik De Clercq, MD, PhD, is Emeritus Professor at the Rega Institute for Medical Research, KU Leuven
Erik De Clercq
First Published February 18, 2019
Featured image credit: Skeletal formula of plerixafor by Fvasconcellos is in the public domain and licensed as CC0.