The molecular pharmacology of AMD11070: An orally bioavailable CXCR4 HIV entry inhibitor

In order to enter and infect human cells HIV must bind to CD4 in addition to either the CXCR4 or the CCR5 chemokine receptor. AMD11070 was the first orally available small molecule antagonist of CXCR4 to enter the clinic. Herein we report the molecular pharmacology of AMD11070 which is a potent inhibitor of X4 HIV-1 replication and the gp120/CXCR4 interaction. Using the CCRF-CEM T cell line that endogenously expresses CXCR4 we have demonstrated that AMD11070 is an antagonist of SDF-1 alpha ligand binding (IC(50) = 12.5 +/- 1.3 nM), inhibits SDF-1 mediated calcium flux (IC(50) = 9.0 +/- 2.0 nM) and SDF-1 alpha mediated activation of the CXCR4 receptor as measured by a Eu-GTP binding assay (IC(50)= 39.8 +/- 2.5 nM) or a [(35)S]-GTP gamma S binding assay (IC(50)= 19.0 +/- 4.1 nM), and inhibits SDF-1 alpha stimulated chemotaxis (IC(50)= 19.0 +/- 4.0 nM). AMD11070 does not inhibit calcium flux of cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, or ligand binding to CXCR7 and BLT(1), demonstrating selectivity for CXCR4. In addition AMD11070 is able to inhibit the SDF-1 beta isoform interactions with CXCR4; and N-terminal truncated variants of CXCR4 with equal potency to wild type receptor. Further mechanistic studies indicate that AMD11070 is an allosteric inhibitor of CXCR4. (C) 2011 Elsevier Inc. All rights reserved.