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

Mosi, Renée; Anastassova, Virginia; Cox, Jennifer H.; Darkes, Marilyn C.; Idzan, Stefan R.; Labrecque, Jean; Lau, Gloria; Nelson, Kim L.; Patel, Ketan; Santucci, Zefferino; Wong, Rebecca S.Y.; Skerlj, Renato T.; Bridger, Gary; Huskens, Dana; Schols, Dominique; Fricker, Simon P.

doi:10.1016/j.bcp.2011.11.020

Cited by 43 publications

(38 citation statements)

References 51 publications

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“…In this regard, Wong et al 76 investigated by site-directed mutagenesis key CXCR4 residues that established interactions with AMD11070 and proposed three different binding modes to explain all interactions between AMD11070 and Tyr45, Trp94, Asp97, Asp171, Asp262 and Glu288. Later, Mosi et al 13 confirmed again those residues as important ones for AMD11070 binding, emphasizing residues Tyr45, Trp94 and Asp97 among them. All these observations agree with our best model proposed for AMD11070 and GSK812397.…”

Section: Figurementioning

confidence: 83%

“…For the small molecules AMD11070 and GSK812397, whose allosteric mechanism is still unclear 13,16 , an analogous approach was proposed to study their interactions. The entire CXCR4 protein surface was explored by blind docking in order to define the binding region, and a second docking analysis by subsites was then performed to refine the allosteric interactions.…”

Section: Small Ligand-protein Blind Dockingmentioning

confidence: 99%

“…On the one hand, pepducin modulators whose allosteric behavior has been experimentally verified 24 and establish peptide-protein interactions with CXCR4. On the other hand, the two small organic molecules, AMD11070 and GSK812397, whose allosteric mechanism is still unclear and requires further experimental investigation 13,16 .…”

Section: Figurementioning

confidence: 99%

“…Later, Mosi et al 13 proposed the antagonist AMD11070 ( Figure 1) as potential inhibitor of the interaction CXCR4-SDF-1, the natural ligand of CXCR4 receptor. AMD11070 would act as a selective noncompetitive inhibitor of isoforms SDF-1α and SDF-1β (or CXCL12a and CXCL12b, respectively) with different modes of action and different IC 50 values.…”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

Planesas

Pérez‐Nueno

Borrell

et al. 2015

Journal of Molecular Graphics and Modelling

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Section: Figurementioning

confidence: 83%

Section: Small Ligand-protein Blind Dockingmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

Planesas

Pérez‐Nueno

Borrell

et al. 2015

Journal of Molecular Graphics and Modelling

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“…The orally bioavailable derivative AMD11070 powerfully impairs CXCL12/CXCR4-mediated chemotaxis in vitro (Mosi et al, 2012; O’Boyle et al, 2013), although phase I/II studies did not warrant further development after safety and pharmacokinetics assessment. BKT140, TG-0054, and POL6326 are currently in clinical evaluation as stem cell mobilizers, for MM, leukemias and lymphomas.…”

Section: Targeting Cxcl12–cxcr4/cxcr7 Axis In Cancer: Rationalementioning

confidence: 99%

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Würth

Bajetto

Harrison

et al. 2014

Front. Cell. Neurosci.

115

128

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Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

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HIV Life Cycle and Inherited Co‐Receptors

Bukrinsky

2014

Encyclopedia of Life Sciences

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Human immunodeficiency virus (HIV) is a Lentivirus of the family Retroviridae , members of which cause a number of neurological and immunological diseases in humans and animals. HIV is the causative agent of the acquired immune deficiency syndrome. The disease is caused by virus‐mediated depletion of CD4+ T lymphocytes, preferentially CCR5‐positive memory T cells. Most of these cells localise to mucosal tissue, in particular gut mucosa, and disruption of the gut mucosal barrier is an early feature of HIV infection that determines the pathogenesis of the disease. More than 20 years of intensive studies identified the molecular mechanisms underlying viral replication and disease pathogenesis and provided the foundation for development of antiviral therapeutics and vaccine. This article provides a brief overview of the HIV life cycle and focuses on receptors that determine viral binding and entry into the target cells. Key Concepts: Virus entry into target cell is initiated by interaction between gp120 and cell receptors. HIV preferentially targets memory CD4+ T cells that localise to mucosal lymphoid tissue, in particular the gut mucosa. HIV replication includes a number of distinct steps: virus–cell fusion and entry, uncoating, reverse transcription and formation of the pre‐integration complex (PIC), PIC nuclear entry and integration, transcription and translation of proviral DNA, viral assembly and release of nascent virions and maturation and formation of infectious virions. To infect a target cell, virus needs to counteract the activity of multiple cellular antiviral factors (APOBEC3, SAMHD1, tetherin), most of which activated by interferon. HIV accessory proteins have evolved to perform this function. Receptors determine not only the first step of HIV interaction with the target cell, but also regulate post‐entry events in viral replication. Characterisation of the molecular mechanisms underlying HIV replication and interaction with the target cells provides an opportunity to develop anti‐HIV therapeutics and vaccine.

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

Cited by 43 publications

References 51 publications

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

Studying the binding interactions of allosteric agonists and antagonists of the CXCR4 receptor

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

HIV Life Cycle and Inherited Co‐Receptors

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