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Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine Phosphatase SHP2 with Anti-Breast Cancer Cell Effects
[Image: see text] The oncogenic property of the Src homology phosphotyrosine phosphatase 2 (SHP2) is well-known, but developing specific inhibitors has been very difficult. Based on our previous reports that showed the importance of acidic residues surrounding SHP2 substrate phosphotyrosines for spe...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542598/ https://www.ncbi.nlm.nih.gov/pubmed/33043190 http://dx.doi.org/10.1021/acsomega.0c02746 |
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author | Hartman, Zachary Geldenhuys, Werner J. Agazie, Yehenew M. |
author_facet | Hartman, Zachary Geldenhuys, Werner J. Agazie, Yehenew M. |
author_sort | Hartman, Zachary |
collection | PubMed |
description | [Image: see text] The oncogenic property of the Src homology phosphotyrosine phosphatase 2 (SHP2) is well-known, but developing specific inhibitors has been very difficult. Based on our previous reports that showed the importance of acidic residues surrounding SHP2 substrate phosphotyrosines for specific recognition, we have rationally designed and chemically synthesized a small-molecule SHP2 inhibitor named 4,4′-(4′-carboxy)-4-nonyloxy-[1,1′-biphenyl]-3,5-diyl)dibutanoic acid (CNBDA). Molecular modeling predicted that CNBDA packs well into the SHP2 active site and makes extended interactions primarily with positively charged and polar amino acids surrounding the active site. In vitro PTPase assays showed that CNBDA inhibits SHP2 with an IC(50) of 5 μM. However, the IC(50) of CNBDA toward SHP1, the close structural homologue of SHP2, was 125 μM, suggesting an approximately 25-fold effectiveness against SHP2 than SHP1. Because SHP2 is known for its positive role in breast cancer (BC) cell biology, we tested the effect of SHP2 inhibition with CNBDA in HER2-positive BC cells. Treatment with CNBDA suppressed cell proliferation in 2D culture, anchorage-independent growth in soft agar, and mammosphere (tumorisphere) formation in suspension cultures in a concentration-dependent manner. Furthermore, CNBDA inhibited EGF-induced signaling and expression of HER2 by inhibiting the PTPase activity of SHP2 in BC cells. These findings suggest that CNBDA is a promising anti-SHP2 lead compound with anti-BC cell effects. |
format | Online Article Text |
id | pubmed-7542598 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-75425982020-10-09 Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine Phosphatase SHP2 with Anti-Breast Cancer Cell Effects Hartman, Zachary Geldenhuys, Werner J. Agazie, Yehenew M. ACS Omega [Image: see text] The oncogenic property of the Src homology phosphotyrosine phosphatase 2 (SHP2) is well-known, but developing specific inhibitors has been very difficult. Based on our previous reports that showed the importance of acidic residues surrounding SHP2 substrate phosphotyrosines for specific recognition, we have rationally designed and chemically synthesized a small-molecule SHP2 inhibitor named 4,4′-(4′-carboxy)-4-nonyloxy-[1,1′-biphenyl]-3,5-diyl)dibutanoic acid (CNBDA). Molecular modeling predicted that CNBDA packs well into the SHP2 active site and makes extended interactions primarily with positively charged and polar amino acids surrounding the active site. In vitro PTPase assays showed that CNBDA inhibits SHP2 with an IC(50) of 5 μM. However, the IC(50) of CNBDA toward SHP1, the close structural homologue of SHP2, was 125 μM, suggesting an approximately 25-fold effectiveness against SHP2 than SHP1. Because SHP2 is known for its positive role in breast cancer (BC) cell biology, we tested the effect of SHP2 inhibition with CNBDA in HER2-positive BC cells. Treatment with CNBDA suppressed cell proliferation in 2D culture, anchorage-independent growth in soft agar, and mammosphere (tumorisphere) formation in suspension cultures in a concentration-dependent manner. Furthermore, CNBDA inhibited EGF-induced signaling and expression of HER2 by inhibiting the PTPase activity of SHP2 in BC cells. These findings suggest that CNBDA is a promising anti-SHP2 lead compound with anti-BC cell effects. American Chemical Society 2020-09-25 /pmc/articles/PMC7542598/ /pubmed/33043190 http://dx.doi.org/10.1021/acsomega.0c02746 Text en This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Hartman, Zachary Geldenhuys, Werner J. Agazie, Yehenew M. Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title | Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine
Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title_full | Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine
Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title_fullStr | Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine
Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title_full_unstemmed | Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine
Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title_short | Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine
Phosphatase SHP2 with Anti-Breast Cancer Cell Effects |
title_sort | novel small-molecule inhibitor for the oncogenic tyrosine
phosphatase shp2 with anti-breast cancer cell effects |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542598/ https://www.ncbi.nlm.nih.gov/pubmed/33043190 http://dx.doi.org/10.1021/acsomega.0c02746 |
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