Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation

Y. Zhang, S. Dayalan Naidu, K. Samarasinghe, G. C. Van Hecke, A. Pheely, T. N. Boronina, R. N. Cole, I. J. Benjamin, P. A. Cole, Y-H Ahn (Lead / Corresponding author), A. T. Dinkova-Kostova (Lead / Corresponding author)

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    Abstract

    Background
    Heat shock protein 90 (HSP90) has a key role in the maintenance of the cellular proteostasis. However, HSP90 is also involved in stabilisation of oncogenic client proteins and facilitates oncogene addiction and cancer cell survival. The development of HSP90 inhibitors for cancer treatment is an area of growing interest as such agents can affect multiple pathways that are linked to all hallmarks of cancer. This study aimed to test the hypothesis that targeting cysteine residues of HSP90 will lead to degradation of client proteins and inhibition of cancer cell proliferation.
    Methods
    Combining chemical synthesis, biological evaluation, and structure-activity relationship analysis, we identified a new class of HSP90 inhibitors. Click chemistry and protease-mass spectrometry established the sites of modification of the chaperone.
    Results
    The mildly electrophilic sulphoxythiocarbamate alkyne (STCA) selectively targets cysteine residues of HSP90, forming stable thiocarbamate adducts. Without interfering with the ATP-binding ability of the chaperone, STCA destabilises the client proteins RAF1, HER2, CDK1, CHK1, and mutant p53, and decreases proliferation of breast cancer cells. Addition of a phenyl or a tert-butyl group in tandem with the benzyl substituent at nitrogen increased the potency. A new compound, S-4, was identified as the most robust HSP90 inhibitor within a series of 19 derivatives.
    Conclusion
    By virtue of their cysteine reactivity, sulphoxythiocarbamates target HSP90, causing destabilisation of its client oncoproteins and inhibiting cell proliferation.
    Original languageEnglish
    Pages (from-to)71-82
    Number of pages12
    JournalBritish Journal of Cancer
    Volume110
    Issue number1
    DOIs
    Publication statusPublished - 7 Jan 2014

    Keywords

    • Hsp90
    • NRF2
    • Cysteine
    • HSF1

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    Dinkova-Kostova, Albena

    • Cellular Medicine - Professor (Teaching and Research) & Professor of Chemical Biology

    Person: Academic

    Cite this

    Zhang, Y., Dayalan Naidu, S., Samarasinghe, K., Van Hecke, G. C., Pheely, A., Boronina, T. N., Cole, R. N., Benjamin, I. J., Cole, P. A., Ahn, Y-H., & Dinkova-Kostova, A. T. (2014). Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation. British Journal of Cancer, 110(1), 71-82. https://doi.org/10.1038/bjc.2013.710