Beyond the Selective Inhibition of Histone Deacetylase 6

Rodrigues, Daniel Alencar; Thota, Sreekanth; Fraga, Carlos A. M.

doi:10.2174/1389557516666160428115959

Cited by 17 publications

(19 citation statements)

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“…However, multiple other cytosolic and nuclear proteins are also regulated by reversible acetylation. Two of the most notable acetylated proteins whose functions are of prime importance in the survival of many tumor cell types are heat shock protein 90 (HSP90) and the p65 subunit of NFκB (Leus, Zwinderman, & Dekker, 2016; Rodrigues, Thota, & Fraga, 2016). …”

Section: Text Elementsmentioning

confidence: 99%

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

Booth

Roberts

Kirkwood

et al. 2018

Advances in Cancer Research

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For several years, it has been known that histone deacetylase inhibitors have the potential to alter the immunogenicity of tumor cells exposed to checkpoint inhibitory immunotherapy antibodies. HDAC inhibitors can rapidly reduce expression of PD-L1 and increase expression of MHCA in various tumor types that subsequently facilitate the antitumor actions of checkpoint inhibitors. Recently, we have discovered that drug combinations which cause a rapid and intense autophagosome formation also can modulate the expression of HDAC proteins that control tumor cell immunogenicity via their regulation of PD-L1 and MHCA. These drug combinations, in particular those using the irreversible ERBB1/2/4 inhibitor neratinib, can result in parallel in the internalization of growth factor receptors as well as fellow-traveler proteins such as mutant K-RAS and mutant N-RAS into autophagosomes. The drug-induced autophagosomes contain HDAC proteins/signaling proteins whose expression is subsequently reduced by lysosomal degradation processes. These findings argue that cancer therapies which strongly promote autophagosome formation and autophagic flux may facilitate the subsequent use of additional antitumor modalities using checkpoint inhibitor antibodies.

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Section: Text Elementsmentioning

confidence: 99%

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

Booth

Roberts

Kirkwood

et al. 2018

Advances in Cancer Research

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“…HDACs are divided into four classes of isozymes, class I (HDACs 1, 2, 3, and 8), class II (HDACs 4, 5, 6, 7, 9, and 10), class III (Sirtuins 1‐7), and class IV (HDAC11) . HDACs from classes I, II, and IV are zinc‐dependent metalloenzymes, whereas class III are nicotinamide adenine dinucleotide (NAD + )‐dependent enzymes …”

Section: Introductionmentioning

confidence: 99%

“…The HDAC6 is considered an atypical member of this family because it is related with its cellular localization (it is found mainly on cytoplasm) and by the fact that HDAC6 has two deacetylase domains . Several HDAC6 inhibitors were described in the literature and some are under clinical evaluation . To understand the structural requirements associated to the selective inhibition of HDAC6, Butler et al developed two homology models for HDAC1 and HDAC6 and they highlighted the differences in the active site on these two enzymes .…”

Section: Introductionmentioning

confidence: 99%

“…[14,15] HDACs from classes I, II, and IV are zinc-dependent metalloenzymes, whereas class III are nicotinamide adenine dinucleotide (NAD + )-dependent enzymes. [15][16][17] The HDAC inhibition is achieved by the use of a well-known pharmacophore which consists of a zinc-binding group (ZBG) to interact with the Zn(II) in the active site, a linker and a cap group to interact with the protein surface. [18] The HDAC inhibition results in the growth arrest, differentiation and apoptosis of many transformed cells.…”

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confidence: 99%

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Modeling zinc‐oxygen coordination in histone deacetylase: A comparison of semiempirical methods performance

Pinheiro

Rodrigues

Sant’Anna

et al. 2018

Int J of Quantum Chemistry

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Semiempirical methods can be applied to calculations of much larger systems than classical ab initio or DFT methods, reaching accuracy sometimes comparable with more advanced levels of theory. These methods are important tools that can be used in research projects focused in structure‐based drug design (SBDD). Thus, a notion of the precision of each method in describing key‐interactions with target receptors is necessary. With this goal in mind, we applied several semiempirical methods (AM1, PM3, PM6, PM6‐D3, PM6‐D3H4, PM6‐DH2, PM6‐DH+, and PM7) for evaluation of the key‐interactions of some zinc‐dependent histone deacetylase (HDAC) inhibitors revealed by crystallographic structures, for which the AM1 and PM7 Hamiltonians generally failed to geometrically describe the bidentate coordination of the pan‐HDAC inhibitors with the Zn(II) ion. In addition, we also applied the same evaluations to Nexturastat A, a histone deacetylase 6 (HDAC6) selective inhibitor, in complex with the HDAC6, to find out how each semiempirical method represent the monodentate coordination profile with the Zn(II) ion when there is a competition with a hydrogen bond in the system. Our results showed a significant difference in the profile of each method and highlighted PM6‐DH2 as the best method for the description of the key‐interactions of Nexturastat A in HDAC6. Our data reinforce the necessity to always compare several semiempirical methods before performing SBDD studies with them.

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“…In the oncology field, two moderately selective HDAC6 inhibitors ACY-1215 and ACY-241 (Fig. 1) have entered cancer clinical trials, alone or in combination with other antitumor agents [20]. In the immunology field, selective inhibition of HDAC6, using hydroxamate-based compounds such as tubacin [21,22], tubastatin A [22–25] and its analogues [26], EJMC-9a [27] or mercaptoacetamide-based compounds such as ACSMCL-2b [28] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a fluorescent probe with HDAC6 selective inhibition

Zhang

Jin

Yao

2017

European Journal of Medicinal Chemistry

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There is increasing interest in discovering HDAC6 selective inhibitors as chemical probes to elucidate the biological functions of HDAC6 and ultimately as new therapeutic agents. Small-molecular fluorescent probes are widely used to detect target protein location and function, identify protein complex composition in biological processes of interest. In the present study, structural modification of the previously reported compound 4MS leads to two novel fluorescent HDAC inhibitors, 6a and 6b. Determination of IC50 values against the panel of Zn2+ dependent HDACs (HDAC1-11) reveals that 6b is a HDAC6 selective inhibitor, which can induce hyperacetylation of tubulin but not histone H4. Importantly, fluorescent and immunofluorescent analyses of cells treated with the proteasome inhibitor MG132 demonstrates that 6b can selectively target and image HDAC6 within the inclusion body, the aggresome. These results identify 6b not only as a HDAC6 selective inhibitor but also as a fluorescent probe for imaging HDAC6 and investigating the roles of HDAC6 in various physiological and pathological contexts.

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Beyond the Selective Inhibition of Histone Deacetylase 6

Cited by 17 publications

References 0 publications

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

Modeling zinc‐oxygen coordination in histone deacetylase: A comparison of semiempirical methods performance

Discovery of a fluorescent probe with HDAC6 selective inhibition

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