SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Methot, Joey L.; Hamblett, Christopher L.; Mampreian, Dawn M.; Jung, Joon; Harsch, Andreas; Szewczak, Alexander A.; Dahlberg, William K.; Middleton, Richard E.; Hughes, Bethany; Fleming, James E.; Wang, Hongmei; Kral, Astrid M.; Ozerova, Nicole; Cruz, Jonathan C.; Haines, Brian B.; Chénard, Mélissa; Kenific, Candia M.; Secrist, J. Paul; Miller, Thomas A.

doi:10.1016/j.bmcl.2008.10.052

Cited by 40 publications

(15 citation statements)

References 30 publications

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“…Compound 6 from Merck, for example, has IC 50 s of 8 and 44 nM against HDAC1 and HDAC2 respectively, while it is significantly less active against HDAC3 with an IC 50 of 1260 nM. Although 6 displayed good oral bioavailability and efficacy in a mouse tumour xenograft model with once daily oral administration, further development was discontinued due to binding of the hERG ion channel [140]. Compound 7 exemplifies another Merck series described in a patent [137], while 8 reported by Methylgene is a thiophene-substituted analogue of the benzamide SNDX-275 in clinical trials.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 96%

Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

Ganesan¹,

Nolan²,

Crabb³

et al. 2009

CCDT

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Histone proteins are subject to a diverse range of post-translational modifications which, along with DNA methylation, play a major role in controlling gene expression, cell division, survival and differentiation. Alterations in these chromatin modifications are thought to contribute to important human diseases including cancer. Inhibition of the enzymes that introduce and remove these chromatin modifications is proving an effective approach to cancer therapy and inhibitors of histone deacetylases and DNA methyltransferases have been approved for use in haematological malignancies. Here we provide a background to the biology of chromatin modifications and review some of the evidence validating histone deacetylases and DNA methyltransferases as targets for anti-cancer drug discovery. We then focus on two of the key issues in this field; the identification of novel inhibitors to overcome shortcomings of first generation agents and the potential role of histone deacetylase and DNA methyltransferase inhibitors in combination therapies for oncology. Finally, we highlight some of the challenges that will need to addressed to further progress the development of epigenetic-based therapies for cancer.

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Section: Histone Deacetylase Inhibitorsmentioning

confidence: 96%

Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

Ganesan¹,

Nolan²,

Crabb³

et al. 2009

CCDT

View full text Add to dashboard Cite

show abstract

“…Merck60 selectively inhibits HDAC1 and HDAC2, thereby increasing histone acetylation and disrupting core gene regulatory architecture in rhabdomyosarcoma ( 129 ). Methot et al ( 130 ) investigated novel selective HDAC1/HDAC2 inhibitors (SHI-1:2), which incorporate a biaryl zinc-binding motif into a nicotinyl scaffold; the optimized SHI-1:2 structure exhibited notable inhibitory activity against HDAC1 and HDAC2, and its specific selectivity for HDAC1/HDAC2 was 100 times higher than that for other HDACs ( 131 ). N-(2-amino-5-substituted phenyl) benzamide significantly induced HCT116 cell death by specifically targeting HDAC2 ( 62 ).…”

Section: Hdac2 In Liver Diseasementioning

confidence: 99%

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

et al. 2021

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Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HdAcs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HdAc2, a member of class I HdAc family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HdAc2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HdAc2 and its physiological and biochemical functions. Secondly, the functional roles of HdAc2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non-alcoholic steatohepatitis. Moreover, abnormal expression of HdAc2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HdAc2 inhibitors and non-coding RNAs relevant to HdAc2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HdAc2 in liver disease.

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“…A comprehensive set of HDAC1 inhibitors characterized by the 2-aminophenylbenzamide scaffold with known IC 50 values that vary over a wide range was collected from the literature [66,67,[79][80][81][82][83][84][85][86][87][88][89][90][91][92] and the bindingDB database [93]. The selection criterion for the compounds to be included in the set was that their HDAC1 inhibition was evaluated using the same fluorescent assay based on the fluorogenic substrate Fluor-de-Lys.…”

Section: Ligands and Data Set Preparationmentioning

confidence: 99%

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

et al. 2020

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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...

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SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2)

Cited by 40 publications

References 30 publications

Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

Epigenetic Therapy: Histone Acetylation, DNA Methylation and Anti-Cancer Drug Discovery

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

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

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