From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents

Abstract

Histone deacetylases (HDACs) are one of two counteracting enzyme families whose activity controls the acetylation state of lysine protein residues, notably those contained in the N-terminal extensions of the core histones. Deregulation of the acetylation state of specific lysine residues has been implicated in a multitude of biologic processes, notably cancer, where HDACs are known to be involved in the control of cell cycle progression, cell survival and differentiation. HDAC inhibitors are being developed as anti-neoplastic agents. Nature has led the way in the development of these compounds, with trichostatin A being the first hydroxamic acid HDAC inhibitor identified. Likewise, the disulfide depsipeptide Romidepsin is currently in clinical trials, while an array of cyclic tetrapeptides HDAC inhibitors have been reported. Rational drug design has allowed these cyclic tetrapeptide to be transformed into equally potent small molecule inhibitors selective for either class I or class II HDACs. While acyclic alkyl ketones have been demonstrated to be selective HDAC 1, 2 and 3 inhibitors with efficacy in xenograft models, trifluoromethyl ketones have been shown to be selective inhibitors for class II HDACs and recently have been revealed to bind in the active site of the enzyme in their hydrated form.

Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

“…The potencies recorded against the class I HDACs 1−3 generally followed the trends observed for apicidin and 2, with the most potent candidates (9 and 10) being ∼6-fold less potent than 2 against HDAC1. Because ethylketone-containing apicidin analogs do not appear to inhibit class IIa HDACs, 39,40 we excluded enzymes of this class in the present investigation. As expected based on inhibition profiles of other ligands containing the ethylketone Zn 2+ -coordinating amino acid, 1−3 all the compounds were inactive against HDAC6, a representative member of the HDAC class IIb (Table 1).…”

Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach

“…Wellknown HDACi such as FK-225497, FR235222, trapoxin A and B, apicidin, chlamydocin all have tetra-peptide caps. [85] There are also reports of pseudo-peptide caps like spirucostatin, YM753, FK-228. [85] Some types of caps are described as follows based on the ring size.…”

“…[85] There are also reports of pseudo-peptide caps like spirucostatin, YM753, FK-228. [85] Some types of caps are described as follows based on the ring size. R12 type tetrapeptides consist of four a-amino acids.…”

Strategies in developing promising histone deacetylase inhibitors

“…So a great number of HDACi have developed with the aim of inhibiting only one subtype of the HDAC family or a single HDAC class. [25][26][27] A. Structural Basis for Subtype Selectivity…”

“…TSA (25, Fig. 5), 83 a cyclic tetrapeptide family, including trapoxin (26,27), 84 HC toxin (28), 85 apicidin (29) 86 and FK228 (9) 87 are all naturally occurring HDACi. Psammmaplin A (PsA, 30) is a natural bromotyrosine derivative that was first isolated from the Psammaplysilla sponge in 1987.…”