Chemical phylogenetics of histone deacetylases

Abstract

The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of Class I and II HDACs as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as non-selective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of a first non-selective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T‐cell lymphoma

“…Romidepsin is a structurally unique, potent, bicyclic class I selective histone deacetylase inhibitor approved for the treatment of all subtypes of relapsed/refractory PTCL 8, 9, 10, 11. In the pivotal phase 2 trial conducted in patients with relapsed/refractory PTCL, romidepsin treatment resulted in durable responses with manageable toxicity 12, 13.…”

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…We next examined the effects of other HDAC inhibitors. We used SAHA, a class I/IIb HDAC inhibitor (28), MS-275, a selective class I HDAC inhibitor (29,30), and MC1568, a selective class II HDAC inhibitor (31,32). As reported recently (33), these HDAC inhibitors did not affect basal Arc mRNA levels (Fig.…”

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

“…HDAC8 is a class I HDAC but diverges significantly from the other class I isoforms 41 and was recently shown to be similar to class IIa isoforms in terms of inhibitor specificity. 39 It was therefore not surprising that compound 9 was 4-fold less potent against HDAC8 as compared to HDAC1. In contrast, compound 9 was ∼3-fold more potent than parent compound 2 against HDAC8, which corresponds with a possible interaction of arginine residues with HDAC8 previously proposed by Mrksich and co-workers based on experiments with histone substrates.…”