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
12/11/2013Pubmed ID
24322890Pubmed Central ID
PMC3887302DOI
10.1038/bjc.2013.710Scopus ID
2-s2.0-84891848414 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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 ATAuthor
Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine TriphosphateAmino 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
