DRUG DISCOVERY AND DEVELOPMENT: THE BICYCLAM AMD3100, A CASE IN POINT

"Chaire Francqui" Inaugural Lecture -- 6/02/03

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DRUG DISCOVERY AND DEVELOPMENT: THE BICYCLAM AMD3100, A CASE IN POINT

LAV Replication, tested by reverse transcriptase (RT) activity in supernatants of T cell cultures, during HPA 23 treatment of a patient with AIDSHPA-23: (NH4)18(NaW21Sb9O86)17

Anti-HIV activity of polyoxometalates

Anti-HIV activity of metalloporphyrins

Anti-HIV activity of JM1657 in MT-4 cells

Anti-HIV activity of bicyclam JM2987

Mutations detected in gp120 of bicyclam-resistant NL4-3 viruses:N269Y R272T S274R Q278H I288V N293H A297T ?FNSTWP385L Q410E S433P V457I

Mechanism of action of bicyclams:interaction with monoclonal antibody binding to CXCR4

Anti-HIV activity profile of AMD3100 correlated with coreceptor use

ANTI-HIV-1 ACTIVITY, INHIBITION OF ANTI-CXCR4 mAb BINDING AND INHIBITION OF SDF-1-INDUCED [Ca2+]i FLUX BY DIFFERENT METAL COMPLEXES OF AMD3100

Antiviral activity of AMD3100 in SCID-hu Thy/Liv mice*

Patients whose CXCR4-using HIV variants were less than 10% at entry

Mobilization of CD34+ cells into peripheral blood:AMD3100 dose response (mean ? SEM)

Peripheral blood CD34+ cell response following administration of G-CSF ? AMD3100 (n = 6 per group; mean ? SEM)

Mobilization and collection of CD34+ cells with AMD3100 and G-CSF

For AMD3100 to be of relevant clinical utility, it would also have to mobilize self-renewing stem cells.

AMD3100 augments incorporation of bone marrow (BM)-derived endothelial progenitor cells (EPCs) into sites of neovascularization after mycocardial infarction (MI) by mobilizing EPCs from BM to peripheral blood.

AMD3100 inhibits stromal derived factor-1 (SDF-1)-dependent migration and proliferation of Acute Lymphoblastic Leukemia (ALL) cells in bone marrow.

The CXCR4-CXCL12 (= SDF-1) circuitry is crucial for the migration of follicular non-Hodgkin’s lymphoma (NHL) cells.

Milestones in the development of the bicyclam AMD3100

Author: Professeur E. De Clercq

Email: tulkens@facm.ucl.ac.be

Home Page: http://www.md.ucl.ac.be/chaire-francqui/slides

Other information:
These slides are for information only. Do not make public use of them without the autorization of Prof. E. De Clercq and the organizers of the "Chaire Francqui". Please, adress your request to <tulkens@facm.ucl.ac.be>

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