title: Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity.
abstract: Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate high-throughput screen, we identified a series of isothiazolone-based HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP-responsive element binding protein-binding protein-associated factor (PCAF) and p300 (1 to >50 micromol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 micromol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2-48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of alpha-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics at the Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stimson
authors.forename: Martin G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Newbatt
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Smith
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Rogers
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Stephen
authors.initials: S
authors.lastname: Gorsuch
authors.forename: Michael
authors.initials: M
authors.lastname: Jarman
authors.forename: Andrew
authors.initials: A
authors.lastname: Bannister
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D006657:Histones; D013844:Thiazoles; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor