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Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation. Br J Cancer 2014 Jan 07;110(1):71-82

Date

12/11/2013

Pubmed ID

24322890

Pubmed Central ID

PMC3887302

DOI

10.1038/bjc.2013.710

Scopus ID

2-s2.0-84891848414   20 Citations

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.

Author List

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

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Amino Acid Sequence
Animals
Breast Neoplasms
Carbamates
Cell Growth Processes
Cell Line, Tumor
Cysteine
Female
HSP72 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
HeLa Cells
Humans
MCF-7 Cells
Mice
Mice, Knockout
Molecular Sequence Data
Molecular Targeted Therapy
Neoplasm Proteins
Sulfhydryl Compounds
Sulfoxides
Up-Regulation
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a