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Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types

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Summary

Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate–4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 μM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.

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Funding

The work was supported by AlJalila Foundation for Medical Education and Research, United Arab Emirates [grant number. AJF201612]

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Authors and Affiliations

  1. Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates

    Cijo George Vazhappilly, Ekram Saleh, Wafaa Ramadan, Varsha Menon, Aya Mudhafar Al-Azawi, Hamadeh Tarazi & Raafat El-Awady

  2. Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt

    Ekram Saleh

  3. College of Pharmacy, University of Sharjah, University City Road, 27272, Sharjah, United Arab Emirates

    Hamadeh Tarazi, Abdel-Nasser El-Shorbagi & Raafat El-Awady

  4. Medicinal Chemistry Department, College of Pharmacy, Assuit University, Assuit, Egypt

    Hajjaj Abdu-Allah & Abdel-Nasser El-Shorbagi

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  1. Cijo George Vazhappilly
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  2. Ekram Saleh
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  8. Abdel-Nasser El-Shorbagi
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  9. Raafat El-Awady
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Correspondence to Raafat El-Awady.

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Author CV declares that he has no conflict of interest. Author ES declares that he has no conflict of interest. Author WR declares that he has no conflict of interest. Author VM declares that he has no conflict of interest. Author AA declares that he has no conflict of interest. Author HT declares that he has no conflict of interest. Author HA declares that he has no conflict of interest. Author AE declares that he has no conflict of interest. Author RE declares that he has no conflict of interest

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Vazhappilly, C., Saleh, E., Ramadan, W. et al. Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types. Invest New Drugs 37, 252–261 (2019). https://doi.org/10.1007/s10637-018-0626-5

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  • DOI: https://doi.org/10.1007/s10637-018-0626-5

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