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 highthroughput screen, we identified a series of isothiazolonebased 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 Mmol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 Mmol/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 A-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. [Mol Cancer Ther 2005;4(10):1521 -32]

Enhanced Expression of PCAF Endows Apoptosis Resistance in Cisplatin-Resistant Cells

“…4 and 5), indicating that PCAF is a potential target for cancer treatment. These results are consistent with the reports that knockdown of PCAF inhibited tumorigenesis and tumor progression in nude mice (27), and inhibitors of PCAF HAT activity decreased cell proliferation (28,29). In addition, E2F1 expression was decreased by the downregulation of PCAF (Fig.…”

Roles of CREB-binding protein (CBP)/p300 in respiratory epithelium tumorigenesis

“…It is garcinol, a polyisoprenylated benzophenone derivative of Garcinia indica fruit rind, and has demonstrated potent inhibitory activity towards histone acetyl-transferases (HATs) both in vitro and in vivo [77]. In addition, a series of isothiazolone-based acetyl-transferase interfering agents were recently reported as being potential small-molecular-mass inhibitors for acetyl-transferases [78].…”

Protein Lysine Acetylated/Deacetylated Enzymes and the Metabolism-Related Diseases

“…Curcumin selectively inhibits KAT3A/3B, rather than KAT2B [49]. Thiazole ketone, screened through high-throughput experiment, is the inhibitor of acetyltransferase KAT2B and KAT3A/3B [50]. Recently it has been developed several…”