YAK540

Clin. used pan and class I HDACi cause severe side effects, whereas class IIa HDACi are less cytotoxic.Here, we present the synthesis and anticancer effects of a series of 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based amides and alkoxyamides derived from the previously reported class IIa HDACi YAK540.The most active class IIa inhibitor 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent showed nanomolar inhibition of the class IIa enzymes 4, 5, 7 (IC₅₀ HDAC4: 12 nM) and high selectivity (selectivity index >318 for HDAC4) over non-class IIa HDACs.Instead of a hydroxamic acid group, 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent has a trifluoromethyloxadiazolyl (TFMO) moiety as a non-chelating Zinc-binding group (ZBG).Applying the Chou-Talalay-method we found an increased synergistic cytotoxic effect of 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent in combination with bortezomib in THP1 cells. 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent in combination with bortezomib enhanced expression of p21 leading to increased caspase-induced apoptosis.Eventually, growth inhibition by 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent of the head-neck cancer cell line Cal27 was increased upon HDAC4 overexpression in Cal27 in cell culture and using the in-vivo chorioallantoic membrane model.The class IIa HDACi 1,2,4-oxadiazole derivative containing N',N'-diethylethane-1,2-diamine substituent outperforms previously described HDAC class IIa inhibitor YAK540 regarding anticancer effects and may constitute a novel option compared to pan and class I HDACi in anticancer combination treatments.

The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs.