Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a <i>N</i>-(2-Aminophenyl)-benzamide Binding Unit

Marson, Charles M.; Matthews, Christopher J.; Atkinson, Sophie; Lamadema, Nermina; Thomas, Nancy

doi:10.1021/acs.jmedchem.5b00545

Cited by 49 publications

(22 citation statements)

References 56 publications

(147 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…86 Marson et al described an oxazoline capping group with a N-(2-aminophenyl) benzamide unit, and compound 19 displayed good inhibitory activity against HDAC3, almost a 13-fold increase compared to HDAC1. 87 Hsieh et al developed a series of HDAC3 selective inhibitors, the target compounds 19A and 19B displayed high HDAC3 potency and selectivity. Especially, they exhibited efficacy in suppressing TNBC cells via the downregulation of b-catenin.…”

Section: Class I Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

Yang

Zhao

et al. 2019

RSC Adv.

View full text Add to dashboard Cite

show abstract

Section: Class I Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

Yang

Zhao

et al. 2019

RSC Adv.

View full text Add to dashboard Cite

show abstract

“…Several ortho -aminoanilides possessing alkyl or alkenyl linkers (Figure 3, RGFP109, RGFP966, and compound 5 ) or a chiral oxazoline cap (Figure 3, compound 6 ) were found to be HDAC3 selective. [37] …”

Section: Alternatives To Hydroxamates For Hdacismentioning

confidence: 99%

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

2015

View full text Add to dashboard Cite

Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan-HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery.

show abstract

“…After the generation of the 3D-QSAR model, a preliminary in silico validation was performed using a large external test set of compounds (113 molecules) selected from the literature [83,84,89,[103][104][105][106] ( Table S2 in the Supplementary Materials) that have not been used for generating and cross validating the model. These compounds were prepared by using Maestro, LigPrep, and MacroModel, adopting the same procedure for preparing the molecules used to derive the model.…”

Section: In Silico 3d-qsar Model Validationmentioning

confidence: 99%

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

et al. 2020

View full text Add to dashboard Cite

Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R 2 = 0.958) and a satisfactory predictive power (Q 2 = 0.822; Q 2 F3 = 0.894). The model was validated (r 2 ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.Molecules 2020, 25, 1952 2 of 20 chromatin structure which concomitantly restricts the accessibility of related transcriptional factors to their target genes, thereby suppressing gene expression including tumor suppressor genes [6][7][8]. The abnormal regulation of this process culminates with the high expression level of HDACs. This event has been observed in the development of several human cancers. Consequently, effective inhibition of HDACs has recently gained importance as a valid therapeutic strategy to reverse aberrant epigenetic changes associated with cancer [9][10][11]. HDAC inhibitors (HDACIs) induce histone hyperacetylation and subsequent transcriptional re-activation of suppressed genes which are correlated with a variety of effects on tumor cells including apoptosis, differentiation, cell cycle arrest, inhibition of proliferation and cytostasis [12,13].The HDAC family comprises 18 isoforms in mammalian cells which are categorized into four main classes (class I-IV) based on their structural and functional characteristics. HDACs belonging to class I (HDAC1-3 and 8), II (HDACs 4-7, 9 and 10) and IV (HDAC11) are all zinc-dependent metalloenzymes, while class III HDACs, also known as the sirtuins (SIRT1-7), requires NAD + as a cofactor for their catalytic function [6,14].Extensive efforts over recent decades have led to the identification of four chemically diverse classes of HDACIs as potent antineoplastic agents including, hydroxamates, benzamides, cyclic peptides, and short-chain fatty acids [3]. The main...

show abstract

Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit

Cited by 49 publications

References 56 publications

Next-generation of selective histone deacetylase inhibitors

Next-generation of selective histone deacetylase inhibitors

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

Contact Info

Product

Resources

About