title: The molecular pharmacology of AMD11070: an orally bioavailable CXCR4 HIV entry inhibitor.
abstract: 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-1α ligand binding (IC50 = 12.5 ± 1.3 nM), inhibits SDF-1 mediated calcium flux (IC50 = 9.0 ± 2.0 nM) and SDF-1α mediated activation of the CXCR4 receptor as measured by a Eu-GTP binding assay (IC50 =39.8 ± 2.5 nM) or a [(35)S]-GTPγS binding assay (IC50 =19.0 ± 4.1 nM), and inhibits SDF-1α stimulated chemotaxis (IC50 =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 BLT1, demonstrating selectivity for CXCR4. In addition AMD11070 is able to inhibit the SDF-1β 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.
authors.affiliation: AnorMED Inc., #200 - 20353 64th Avenue, Langley, BC V2Y 1N5, Canada.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Mosi
authors.forename: Virginia
authors.initials: V
authors.lastname: Anastassova
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cox
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Darkes
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Idzan
authors.forename: Jean
authors.initials: J
authors.lastname: Labrecque
authors.forename: Gloria
authors.initials: G
authors.lastname: Lau
authors.forename: Kim L
authors.initials: KL
authors.lastname: Nelson
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Santucci
authors.forename: Rebecca S Y
authors.initials: RS
authors.lastname: Wong
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D002082:Butylamines; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D019380:Anti-HIV Agents; D001562:Benzimidazoles; D002082:Butylamines; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor