Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs)

Abstract

The modulation of epigenetic targets has recently become an attractive strategy for drug discovery. Among these, it is the inhibition of histone deacetylases (HDACs) that has received the most attention. Numerous HDAC inhibitors have advanced to clinical trials and two have received FDA approval as anticancer agents. This chapter reviews natural and synthetic inhibitors of zinc-dependent HDACs that contain a macrocyclic scaffold including the trapoxin and apicidin cyclic tetrapeptides, the FK228 depsipeptide family, the azumamides and fully synthetic macrocycles.

Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

“…While trichostatin A with its simple aromatic cap is a nonselective HDAC inhibitor, both romidepsin and largazole contain larger macrocyclic caps that contribute to their enzyme affinity as well as enable isoform discrimination. 43 The importance of augmenting zinc and substrate channel binding with additional interactions is illustrated by the marine sponge natural product azumamide E (6). Synthetic carboxylic acids have fared poorly as HDAC inhibitors despite their successful use as zinc binding groups against other metalloenzymes.…”

Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness

“…We tested three inhibitors: FK228 (HDAC1–3, 10-, and 11-selective) (Ganesan, 2015), SAHA (pan-HDAC), and Merck60 (HDAC1 and HDAC2 selective) (Methot et al, 2008). In HEK293 cell cultures, all three inhibitors increased the expression of nearly all eight REST targets that were selected for qRT-PCR analysis based on reduced expression of their orthologues in the ear and brain of the Rest +/ΔEx4 mouse (Figure S5A).…”

Romidepsin and the Zinc‐Binding Thiol Family of Natural Product HDAC Inhibitors

“…The promising biological results obtained with FR901228 in preclinical development led to a Cooperative Research and Development Agreement (CRADA) between Fujisawa and the American National Cancer Institute (NCI) in 1998. The compound was now known as FK228 at Fujisawa and NSC 630176 at the NCI and also referred to as 'depsipeptide' to distinguish it from other HDAC inhibitors of natural or synthetic origin [14]. This terminology persists in the literature although depsipeptide merely refers to a functional group shared by many molecules regardless of biological function and does not hint at FK228's unique thiol zinc-binding group compared to other HDAC inhibitors in clinical development.…”