Discovery of Novel Non‐Cyclam Polynitrogenated CXCR4 Coreceptor Inhibitors

Pettersson, Sune; Pérez‐Nueno, Violeta I.; Ros-Blanco, Laia; Bellacasa, Raimon Puig de la; Rabal, Obdulia; Batllori, Xavier; Clotet, Bonaventura; Clotet‐Codina, Imma; Armand‐Ugón, Mercedes; Esté, José A.; Borrell, José I.; Teixidó, Jordi

doi:10.1002/cmdc.200800145

Cited by 16 publications

(35 citation statements)

References 92 publications

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“…This is additional evidence these molecules may be associated with tumor resistance to anti-angiogenic therapy. The expression of SDF1α and CXCR4 has been strongly implicated in tumor growth, promoting cell migration and the recruitment of cells implicated in the revascularization process in tumors [17, 44–47]; this strongly suggested that SDF1/CXCR4 assists tumors in evading anti-angiogenic therapy. The microenvironment contribution in GBM development is increasingly emphasized.…”

Section: Discussionmentioning

confidence: 99%

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

et al. 2017

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BackgroundGlioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity.MethodsThe effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd).ResultsThe in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFβ1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect.ConclusionsThe CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

et al. 2017

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“…[17] Based on this evidence, we designed a library of new monocyclam derivatives which combine the cyclam ring with the diamines used in our previous work. [17] A selection of the presumably most active compounds (2 and 3) was accomplished with published virtual screening methods. [18] Here, we report on the synthesis, binding mode studies and anti-HIV activity of these two novel monocyclam derivatives.…”

Section: Rational Design Of Monocyclam Derivativesmentioning

confidence: 99%

Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design, Synthesis, Anti‐HIV Evaluation, and Their Interaction with the CXCR4 Co‐receptor

Pettersson¹,

Pérez‐Nueno²,

Mena³

et al. 2010

ChemMedChem

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The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus-cell entry/fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC(50) values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site-directed mutagenesis data on the CXCR4 co-receptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non-cyclam compounds from which the monocyclams are derived, and the well-known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.

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“…MSX-122 ( Fig. 1) is the lead compound of this class [25,26]. Orally bioavailable functionalized isothioureas were found to be potent and selective CXCR4 antagonists ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

Neves

Simões

Melo

2010

J Comput Aided Mol Des

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CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance. These results provide an important tool for structure-based drug design and virtual ligand screening of new CXCR4 antagonists.

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Discovery of Novel Non‐Cyclam Polynitrogenated CXCR4 Coreceptor Inhibitors

Cited by 16 publications

References 92 publications

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

The brain-penetrating CXCR4 antagonist, PRX177561, increases the antitumor effects of bevacizumab and sunitinib in preclinical models of human glioblastoma

Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design, Synthesis, Anti‐HIV Evaluation, and Their Interaction with the CXCR4 Co‐receptor

Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach

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