Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

Abstract

Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.

Development of the first non-hydroxamate selective HDAC6 degraders

“…A few alternative ZBGs, for example, mercaptoacetamides, thiols, and trifluoromethyl ketones enabled potent HDAC6 inhibition but lower selectivity than hydroxamic acids. 14 In 2018, Yates 15 disclosed a new type of highly potent HDAC6 selective inhibitors based on pyrimidine linkers and the 2-(difluoromethyl)-1,3,4oxadiazole (DFMO) group as ZBG (for representative structures, see Fig. S1, ESI).…”

Development of the first non-hydroxamate selective HDAC6 degraders

“…A few alternative ZBGs, for example, mercaptoacetamides, thiols, and trifluoromethyl ketones enabled potent HDAC6 inhibition but exhibited lower selectivity than hydroxamic acids. 14 In 2018, Yates 15 disclosed a new type of highly potent HDAC6 selective inhibitors based on pyrimidine linkers and the 2-(difluoromethyl)-1,3,4-oxadiazole group as ZBG (for representative structures, see Fig. S1, ESI).…”

Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors

“…Histone deacetylases (HDACs) are Zn-containing enzymes that play a crucial role in anticancer therapy [ 17 ]. Fortunately, the zinc-binding groups (ZBGs) of HDAC inhibitors are different from those reported for CAs, as per the recent reviews [ 18 , 19 ]. The ZBGs of HDACIs are classified into classical and nonclassical groups.…”