5-(Trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based highly selective class IIa HDAC inhibitors exhibit synergistic anticancer activity in combination with bortezomib

Abstract

Clinically 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 1a 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, 1a 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 1a in combination with bortezomib in THP1 cells. 1a in combination with bortezomib enhanced expression of p21 leading to increased caspase-induced apoptosis. Eventually, growth inhibition by 1a 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 1a 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.

Keywords: Bortezomib; Combination therapy; Proteasome inhibitors; Selective class IIa HDAC inhibitors; Synergistic anti-cancer activity.