Differential protein acetylation induced by novel histone deacetylase inhibitors

Glaser, Keith B.; Li, J.; Pease, Lori J.; Staver, Michael J.; Marcotte, Patrick A.; Guo, Jun; Frey, Robin R.; Garland, Robert B.; Heyman, H. Robin; Wada, Carol K.; Vasudevan, Anil; Michaelides, M.R.; Davidsen, Steven K.; Curtin, Michael L.

doi:10.1016/j.bbrc.2004.10.082

Cited by 58 publications

(40 citation statements)

References 34 publications

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“…R306465 differs from other hydroxamate-based inhibitors currently in clinical development in that it has preferential activity towards class I HDACs compared to HDAC6. So far, for the HDAC inhibitors in clinical development, HDAC1 selectivity has been reported only for non-hydroxamic acid-based HDAC inhibitors, such as the benzamide MS-275 (Blagosklonny et al, 2002;Hu et al, 2003;Glaser et al, 2004). In our hands, however, MS-275 did not inhibit the activity of HDAC1 complexes precipitated from tumour cells and induced cellular H3 acetylation only at very high concentrations.…”

Section: Discussionmentioning

confidence: 53%

“…Histone deacetylase inhibitors in clinical development were found to be either equipotent against HDAC6 and class I HDACs (panobinostat) or show preferential activity towards HDAC6 (vorinostat). Selectivity of vorinostat towards HADC6 has not been observed previously, possibly because most previous studies were performed with a generic 'Fluor-de-Lys' HDAC substrate Glaser et al, 2004). When using HDAC isotype-specific substrates, R306465 showed poor inhibition of deacetylation of an HDAC6-specific synthetic substrate, which was confirmed while analysing HDAC1 -3 (H3) and HDAC6 substrates (Tubulin, Hsp90) in A2780 ovarian carcinoma cells.…”

Section: Discussionmentioning

confidence: 68%

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R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 68%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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“…The use of a phenylthiazole as the CAP group for HDAC inhibitors has previously been reported by Glaser et al [28] using either an α-ketoamide or a hydroxamate as the ZBG. As is readily apparent from Table 2, the phenylthiazole HDACIs are more potent inhibitors than the biphenyl HDACIs found in Table 1, with IC 50 values for HDAC1 close to that shown by TSA.…”

Section: Hdac Isoform Inhibition Assaymentioning

confidence: 99%

“…The simple phenylthiazole ligand and some of its substituted counterparts were first reported by Abbott in 2004, and such compounds appear to act as relatively potent, pan-HDACs inhibitors. [12] The synthesis of the glycine bearing phenylthiazole analog is also outlined in Scheme 3. Thus, 14b was coupled with BOC-Gly-OH using EEDQ, and then the ester 18 was hydrolyzed by LiOH to afford acid 19.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…[11] In order to learn more about the role that the individual HDACs play in cell growth and/or differentiation, neuronal protection, and apoptosis, it is important to develop agents showing selectivity for individual isoforms or a small subset of these isoforms. While some rather limited degree of isoform selectivity has been shown by a few compounds, [12] this problem of identifying selective inhibitors is far from solved, and the problem is rather complicated by the functional interactions between different HDAC isoforms together with the fromation of co-repressor complexes with other proteins that could possibly alter their interaction with various small molecule inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

et al. 2008

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The histone deacetylases (HDACs) are able to regulate gene expression and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the possibility to achieve some measure of isoform selectivity in the inhibition of the HDACs, we prepared a small series of 2,4′-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low nM potency in the HDAC inhibition assays and display micromolar to low nanomolar IC 50 values when tested against five pancreatic cancer cell lines. The isoform selectivity of these ligands for the Class I HDACs (HDAC1-3 and 8) and Class IIb HDACs (HDAC6 and HDAC10) together with QSAR studies of their correlation with the lipophilicity are presented. Of particular interest is the HDAC6 selectivity of the mercaptoacetamides.

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Epigenetic Targets in Drug Discovery: Cell‐Based Assays for HDAC Inhibitor Hit Validation

Jung

Yong

Velena

et al. 2009

Epigenetic Targets in Drug Discovery

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IntroductionInhibitors of histone deacetylases (HDACs) are emerging as novel potential therapeutic agents for patients with cancers and/or neurological diseases. A number of HDAC inhibitors (HDACIs) have already entered clinical trials; and recently the hydroxamic acid derivative Vorinostat, suberoylanilide hydroxamic acid (SAHA), received FDA approval for the treatment of patients with cutaneous T-cell lymphoma. Furthermore, improved understanding of the roles of various HDAC isoforms in cell processes and in diseases contribute to the strategies for developing second generation inhibitors offering enhanced target specificity and improved toxicity profiles. Reports presenting new classes of HDAC inhibitors with isoform specificity have been developed utilizing in vitro enzymatic screening assays. However, in vitro enzyme activities have limitations and full assessment of isoform specificities of HDACIs requires the application of assays based on functions of multiprotein complexes that may include HDACs and/or other cofactors. In this setting, cell-based assays are needed to permit selective profiling and screening of HDACIs for relative HDAC isoform inhibitory activities for rational drug discovery. The approaches that have been used to assess molecular and biological actions of HDACIs in cells and tissues are reviewed in this chapter.Histone deacetylases are metalloenzymes that catalyze the deacetylation of the e-lysine of acetylated substrates, including histones and nonhistone proteins. Eighteen human HDACs have been identified to date and these are divided into four classes, based on structure, sequence homology, and domain organization. Class I consists of HDACs 1, 2, 3 and 8. These HDACs are homologous to yeast RPD3 [1,2]. Class I HDACs are expressed primarily in the nucleus and play a role in cell proliferation [3,4]. Class II HDACs include isoforms 4, 5, 6, 7, 9 and 10 and are further subdivided into IIa (HDACs 4,5,7,9) and IIb (HDACs 6, 10) [5]. These enzymes are characterized by a large NH 2 -terminal domain or a second catalytic site and play roles in cellular differentiation and development [6]. Class III HDACs were originally

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Differential protein acetylation induced by novel histone deacetylase inhibitors

Cited by 58 publications

References 34 publications

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

Epigenetic Targets in Drug Discovery: Cell‐Based Assays for HDAC Inhibitor Hit Validation

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