Format

Send to

Choose Destination
See comment in PubMed Commons below
Br J Cancer. 2014 Jan 7;110(1):71-82. doi: 10.1038/bjc.2013.710. Epub 2013 Dec 5.

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

Author information

1
Division of Cancer Research, Jacqui Wood Cancer Centre, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
2
Department of Chemistry, Wayne State University, Detroit, MI, USA.
3
Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
University of Utah, School of Medicine Health Sciences Center, Salt Lake City, UT, USA.
5
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
1] Division of Cancer Research, Jacqui Wood Cancer Centre, Medical Research Institute, University of Dundee, Dundee, Scotland, UK [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

PMID:
24322890
PMCID:
PMC3887302
DOI:
10.1038/bjc.2013.710
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center