Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

Abstract

Trichostatin A (TSA) and trapoxin (TPX) are potent inhibitors of histone deacetylases (HDACs). TSA is proposed to block the catalytic reaction by chelating a zinc ion in the active-site pocket through its hydroxamic acid group. On the other hand, the epoxyketone is suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound cyclic hydroxamic acid-containing peptide (CHAP) 1 inhibited HDAC1 at low nanomolar concentrations. The HDAC1 inhibition by CHAP1 was reversible as it was by TSA, in contrast to the irreversible inhibition by TPX. CHAP with an aliphatic chain length of five, which corresponded to that of acetylated lysine, was stronger than those with other lengths. These results suggest that TPX is a substrate mimic and that the replacement of the epoxyketone with the hydroxamic acid converted TPX to an inhibitor chelating the zinc like TSA. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, whereas TSA inhibited these HDACs to a similar extent. HDAC6 inhibition by TPX at a high concentration was reversible, probably because HDAC6 is not alkylated by TPX. We further synthesized the counterparts of all known naturally occurring cyclic tetrapeptides containing the epoxyketone. HDAC1 was highly sensitive to all these CHAPs much more than HDAC6, indicating that the structure of the cyclic tetrapeptide framework affects the target enzyme specificity. These results suggest that CHAP is a unique lead to develop isoform-specific HDAC inhibitors.

Class II histone deacetylases: versatile regulators

“…In HDAC10, the C-terminal catalytic domain lacks the active pocket residues required for enzymatic activity. The enzymatic activities of HDAC6 and HDAC10 are more resistant to trapoxin and sodium butyrate than those of class I and class IIa HDACs [9,84]. Deletion of the second incomplete catalytic domain of HDAC10 restores its sensitivity to both sodium butyrate and trapoxin, suggesting that the two HDAC domains functionally interact [9].…”

Subtype Selective Substrates for Histone Deacetylases

“…This would be much easier than using immunoprecipitated subtypes and a nonselective substrate. We compared the subtype selectivities of two TSA-like inhibitors 17 M344 (16b) and M360 (16c) and three structurally unrelated cyclotetrapeptide inhibitors (CHAPs 18,19 ) ( Figure 4). M344 (16b) was selective for HDAC6 vs HDAC1 (IC 50 , 88 vs 249 nM).…”

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

“…Among the more recently synthesized molecules belonging to this class of HDIs are the CHAP compounds, able to exert their inhibitory effect even at nanomolar concentrations (15,16). It has also been shown that newly synthesized sulphonamide hydroxamic acid products were able, at micromolar concentrations, to exert antiproliferative action against human colon tumor cells in vitro (17).…”