Citarinostat (ACY241) is an orally available, and highly selective inhibitor of HDAC6, showing an IC50 of 2.6 nM. Its selectivity extends across other HDAC isoforms as well, with IC50 values of 35 nM, 45 nM, 46 nM, and 137 nM for HDAC1, HDAC2, HDAC3, and HDAC8, respectively, suggesting its potential for anticancer applications[1].
体内研究
Furthermore, in vivo studies reveal that Citarinostat, dosed at 50 mg/kg via intraperitoneal injection once daily for five days followed by a two-day break for three weeks, significantly inhibits tumor growth. This effect is observed in female athymic nude mice when Citarinostat is used in conjunction with NSC 125973, highlighting its therapeutic potential in cancer treatment when possibly combined with other anticancer agents.
体外研究
When administered to A2780 cells at a concentration of 300 nM for 24 hours, Citarinostat leads to notable hyperacetylation of α-tubulin, indicating the inhibition of HDAC6's tubulin deacetylase activity. Conversely, significant hyperacetylation of histone H3, a Class I HDAC target, is observed only at concentrations exceeding 1 μM. This delineates Citarinostat's capability for selective inhibition of HDAC6 at lower doses, while higher doses inhibit Class I HDAC isozymes[1].
In terms of cytotoxicity, Citarinostat's IC50 values span from 4.6 to 6.1 μM in A2780 and TOV-21G ovarian cancer cells, as well as in MDA-MB-231 breast cancer cells. The data indicate that lower doses of Citarinostat up to 3 μM modestly reduce cell proliferation without triggering apoptosis. However, a higher dose of 10 μM markedly induces apoptosis and entirely halts proliferation[1].
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