Molecules, Vol. 24, Pages 3739: Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity

Molecules, Vol. 24, Pages 3739: Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity Molecules doi: 10.3390/molecules24203739 Authors: Jianrong Sang Ketav Kulkarni Gabrielle M. Watson Xiuquan Ma David J. Craik Sónia T. Henriques Aaron G. Poth Aurélie H. Benfield Jacqueline A. Wilce Grb7 is an adapter protein, overexpressed in HER2+ve breast and other cancers, and identified as a therapeutic target. Grb7 promotes both proliferative and migratory cellular pathways through interaction of its SH2 domain with upstream binding partners including HER2, SHC, and FAK. Here we present the evaluation of a series of monocyclic and bicyclic peptide inhibitors that have been developed to specifically and potently target the Grb7 SH2-domain. All peptides tested were found to inhibit signaling in both ERK and AKT pathways in SKBR-3 and MDA-MB-231 cell lines. Proliferation, migration, and invasion assays revealed, however, that the second-generation bicyclic peptides were not more bioactive than the first generation G7-18NATE peptide, despite their higher in vitro affinity for the target. This was found not to be due to steric hindrance by the cell-permeability tag, as ascertained by ITC, but to differences in the ability of the bicyclic peptides to interact with and penetrate cellular membranes, as determined using SPR and mass spectrometry. These studies reveal that ...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research

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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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