ITSA-1 (ITSA1)

ITSA-1 (ITSA1) is an HDAC activator through trichostatin A (TSA) suppression.

Trichostatin A (TSA), a streptomyces metabolite, can specifically inhibit mammalian histone deacetylase at a nanomolar concentration causing accumulation of highly acetylated histone molecules in mammalian cells.

In vitro: Previous study reported that in murine embryonic stem cells, TSA treatment for 23 hours inhibited BrdU incorporation compared with the control. TSA-pretreated cells incubated with ITSA1, however, could incorporate BrdU at concentrations where it was inhibited by TSA alone. Moreover, ITSA1 treatment was able to revert the TSA-arrested population to a normal cell cycle distribution. TSA treatment at 300 nM to A549 cells for 2 hours noticeably increased the levels of acetyl-histone H3, whereas subsequent incubation with ITSA1 at 50 μM for 2 hours reduced histone acetylation to the baseline level. In addition, cells pretreated with ITSA1 before addition of TSA showed increased acetylation levels, which was a characteristic of TSA treatment alone. These results suggested that the target of ITSA1 was not present until induced by TSA. Furthermore, the ITSA1 treatment alone at 50 or 100 μM was not effective on HDAC activity, demonstrating that ITSA1 could directly affect HDAC function [1].

In vivo: So far, there is no animal in vivo data reported.

Clinical trial: Up to now, ITSA-1 (ITSA1) is still in the preclinical development stage.

Reference:
[1] Koeller KM, Haggarty SJ, Perkins BD, Leykin I, Wong JC, Kao MC, Schreiber SL.  Chemical genetic modifier screens: small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation. Chem Biol. 2003 May;10(5):397-410.