title: Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation.
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.
  
  
  CONCLUSIONS
  By virtue of their cysteine reactivity, sulphoxythiocarbamates target HSP90, causing destabilisation of its client oncoproteins and inhibiting cell proliferation.
authors: Division of Cancer Research, Jacqui Wood Cancer Centre, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors: Y
authors: Y
authors: Zhang
authors: Division of Cancer Research, Jacqui Wood Cancer Centre, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors: S
authors: S
authors: Dayalan Naidu
authors: Department of Chemistry, Wayne State University, Detroit, MI, USA.
authors: K
authors: K
authors: Samarasinghe
authors: Department of Chemistry, Wayne State University, Detroit, MI, USA.
authors: G C
authors: GC
authors: Van Hecke
authors: Division of Cancer Research, Jacqui Wood Cancer Centre, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors: A
authors: A
authors: Pheely
authors: Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: T N
authors: TN
authors: Boronina
authors: Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: R N
authors: RN
authors: Cole
authors: University of Utah, School of Medicine Health Sciences Center, Salt Lake City, UT, USA.
authors: I J
authors: IJ
authors: Benjamin
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: P A
authors: PA
authors: Cole
authors: Department of Chemistry, Wayne State University, Detroit, MI, USA.
authors: Y-H
authors: YH
authors: Ahn
authors: 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.
authors: A T
authors: AT
authors: Dinkova-Kostova
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002219:Carbamates / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002219:Carbamates; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D009363:Neoplasm Proteins; D013438:Sulfhydryl Compounds; D013454:Sulfoxides; D000255:Adenosine Triphosphate; D003545:Cysteine