Novel peptide mimetic small molecules of the HAV motif in N-cadherin inhibit N-cadherin-mediated neurite outgrowth and cell adhesion

Burden-Gulley, Susan M.; Gates, Theresa J.; Craig, Sonya; Lou, Sara F.; Oblander, Samantha A.; Howell, Scott J.; Gupta, Mukur; Brady‐Kalnay, Susann M.

doi:10.1016/j.peptides.2009.09.013

Cited by 24 publications

(19 citation statements)

References 31 publications

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“…The humanisation of N-cadherin-blocking antibodies such as GC-4 may represent one such approach to utilise N-cadherin as a therapeutic target. Moreover, the development of next-generation N-cadherin-targeting small molecules with enhanced stability over existing peptide inhibitors show promise as potent inhibitors of N-cadherin function [ 198 – 200 ]. It remains to be seen whether these compounds have efficacy as anti-cancer agents.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer

et al. 2018

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In many types of solid tumours, the aberrant expression of the cell adhesion molecule N-cadherin is a hallmark of epithelial-to-mesenchymal transition, resulting in the acquisition of an aggressive tumour phenotype. This transition endows tumour cells with the capacity to escape from the confines of the primary tumour and metastasise to secondary sites. In this review, we will discuss how N-cadherin actively promotes the metastatic behaviour of tumour cells, including its involvement in critical signalling pathways which mediate these events. In addition, we will explore the emerging role of N-cadherin in haematological malignancies, including bone marrow homing and microenvironmental protection to anti-cancer agents. Finally, we will discuss the evidence that N-cadherin may be a viable therapeutic target to inhibit cancer metastasis and increase tumour cell sensitivity to existing anti-cancer therapies.

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Section: Discussionmentioning

confidence: 99%

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer

et al. 2018

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“…Consequently in future studies, we will aim to design and test small peptides targeting the FGFR binding site. Indeed, a small peptide encoding the N-cadherin binding site in EC1, producing an HAV peptide which antagonises N-cadherin, is being trialed as a cancer chemotherapeutic, 18 demonstrating that this approach has potential for clinical use.…”

Section: Discussionmentioning

confidence: 99%

EC4, a truncation of soluble N-cadherin, reduces vascular smooth muscle cell apoptosis and markers of atherosclerotic plaque instability

Lyon

Johnson

White

et al. 2014

Molecular Therapy - Methods & Clinical Development

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Atherosclerotic plaque instability is precipitated by vascular smooth muscle cell apoptosis in the fibrous cap, weakening it and leading to plaque rupture. We previously showed that reducing smooth muscle cell apoptosis with soluble N-cadherin (SNC) increased features of plaque stability. We have now identified the active site of SNC and examined whether a truncated form containing this site retains the antiapoptotic effect. SNC was mutated to prevent interaction with N-cadherin or fibroblast growth factor receptor (FGFR). Interaction with FGFR in the extracellular (EC) 4 domain of SNC was essential for the antiapoptotic effect. Therefore, we made a truncated form consisting of the EC4 domain. EC4 significantly reduced smooth muscle cell, macrophage, and endothelial cell apoptosis in vitro by ~70%, similar to SNC. Elevation of plasma levels of EC4 in male apolipoprotein E–deficient mice with existing atherosclerosis significantly reduced apoptosis in brachiocephalic artery plaques by ~50%. EC4 reduced plaque size and the incidence of buried fibrous layers and the macrophage:smooth muscle cell ratio (surrogate markers of plaque instability). Interaction of EC4 with FGFR induced potent antiapoptotic signaling in vitro and in vivo. EC4 modulates atherosclerosis in mice demonstrating its therapeutic potential for retarding plaque size and instability.

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“…13 As a result, libraries of cyclic peptides based on HAV or INP sequences and of non-peptide HAV mimics were developed and tested for their ability to inhibit the cadherin dimerization process. [28][29][30] Based on these studies, the antagonist peptide N-Ac-CHAVC-NH2 (ADH-1 or Exherin™) is now in phase I clinical trials in patients with N-cadherinexpressing solid tumors. [31][32][33] However, its binding interface and mechanism of inhibition are still totally unknown.…”

Section: Figurementioning

confidence: 99%

Crystal Structure of Human E-Cadherin-EC1EC2 in Complex with a Peptidomimetic Competitive Inhibitor of Cadherin Homophilic Interaction

et al. 2016

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Cadherins are transmembrane cell adhesion proteins whose aberrant expression often correlates with cancer development and proliferation. We report the crystal structure of an E-cadherin extracellular fragment in complex with a peptidomimetic compound that was previously shown to partially inhibit cadherin homophilic adhesion. The structure reveals an unexpected binding mode and allows the identification of a druggable cadherin interface, thus paving the way to a future structure-guided design of cell adhesion inhibitors against cadherin-expressing solid tumors.

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Novel peptide mimetic small molecules of the HAV motif in N-cadherin inhibit N-cadherin-mediated neurite outgrowth and cell adhesion

Cited by 24 publications

References 31 publications

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer

N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer

EC4, a truncation of soluble N-cadherin, reduces vascular smooth muscle cell apoptosis and markers of atherosclerotic plaque instability

Crystal Structure of Human E-Cadherin-EC1EC2 in Complex with a Peptidomimetic Competitive Inhibitor of Cadherin Homophilic Interaction

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