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, Robert N Cole, I. J. Benjamin, P. A. Cole, Y. H. Ahn, A. T. Dinkova-Kostova

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)71-82
Number of pages12
JournalBritish Journal of Cancer
Volume110
Issue number1
DOIs
StatePublished - 2014

Fingerprint

HSP90 Heat-Shock Proteins
Proteolysis
Cysteine
Cell Proliferation
Neoplasms
Alkynes
Oncogene Proteins
Thiocarbamates
Click Chemistry
Structure-Activity Relationship
Mass Spectrometry
Cell Survival
Peptide Hydrolases
Nitrogen
Adenosine Triphosphate
Maintenance
Breast Neoplasms

Keywords

  • cysteine
  • HSF1
  • Hsp90
  • NRF2

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhang, Y., Dayalan Naidu, S., Samarasinghe, K., Van Hecke, G. C., Pheely, A., Boronina, T. N., ... 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

Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation. / Zhang, Y.; Dayalan Naidu, S.; Samarasinghe, K.; Van Hecke, G. C.; Pheely, A.; Boronina, T. N.; Cole, Robert N; Benjamin, I. J.; Cole, P. A.; Ahn, Y. H.; Dinkova-Kostova, A. T.

In: British Journal of Cancer, Vol. 110, No. 1, 2014, p. 71-82.

Research output: Contribution to journalArticle

Zhang, Y, Dayalan Naidu, S, Samarasinghe, K, Van Hecke, GC, Pheely, A, Boronina, TN, Cole, RN, Benjamin, IJ, Cole, PA, Ahn, YH & Dinkova-Kostova, AT 2014, 'Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation', British Journal of Cancer, vol. 110, no. 1, pp. 71-82. https://doi.org/10.1038/bjc.2013.710
Zhang, Y. ; Dayalan Naidu, S. ; Samarasinghe, K. ; Van Hecke, G. C. ; Pheely, A. ; Boronina, T. N. ; Cole, Robert N ; Benjamin, I. J. ; Cole, P. A. ; Ahn, Y. H. ; Dinkova-Kostova, A. T. / Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation. In: British Journal of Cancer. 2014 ; Vol. 110, No. 1. pp. 71-82.
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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.",
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AU - Dayalan Naidu, S.

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AU - Van Hecke, G. C.

AU - Pheely, A.

AU - Boronina, T. N.

AU - Cole, Robert N

AU - Benjamin, I. J.

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AU - Ahn, Y. H.

AU - Dinkova-Kostova, A. T.

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