2-(Difluoromethyl)-1,3,4-oxadiazoles: The Future of Selective Histone Deacetylase 6 Modulation?

Histone deacetylase 6 (HDAC6) is an important target for the treatment of oncological and non-oncological diseases. Established HDAC6 inhibitors feature a hydroxamic acid as a zinc-binding group (ZBG) and thus possess mutagenic and genotoxic potential. Recently, the 2-(difluoromethyl)-1,3,4-oxadiazole (DFMO) group emerged as a novel ZBG. In this Viewpoint, we summarize the discovery of the mode of action of DFMOs. Additionally, we discuss opportunities and challenges in the journey toward the clinical development of DFMO-based drugs for the treatment of HDAC6-driven diseases.