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Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Bonomi R, Mukhopadhyay U, Shavrin A, Yeh HH, Majhi A, Dewage SW, Najjar A, Lu X, Cisneros GA, Tong WP, Alauddin MM, Liu RS, Mangner TJ, Turkman N, Gelovani JG - PLoS ONE (2015)

Bottom Line: Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors.PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo.Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.

ABSTRACT
Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa-specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.

No MeSH data available.


The structures of compounds and docking scores with HDAC8, a HDAC Class I enzyme.A lower docking score indicates higher affinity.
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pone.0133512.g007: The structures of compounds and docking scores with HDAC8, a HDAC Class I enzyme.A lower docking score indicates higher affinity.

Mentions: Structural comparison of active sites of HDACs class I and IIa enzymes may explain the mechanism of selectivity of FAHA, DFAHA and TFAHA for HDACs class IIa. The major differences between HDACs class I (1, 2, 3 and 8) and HDACs class IIa (4, 5, 7 and 9) is the substitution of His976 (class IIa) for Tyr306 (class I) in the catalytic site. This change in amino acid residues in the catalytic site results in negligible intrinsic deacetylase activity but has two important structural consequences: the change in size of the active site, and the removal of a hydrogen bond donor site. Class I HDACs have a smaller catalytic cavity than class IIa enzymes, which explains why larger leaving groups do not fit in the catalytic site and are not cleaved by these enzymes. The docking results for HDAC 8 (class I) shown in Fig 7, demonstrate that increasing the size of the leaving group (acetyl < trifluoroacetyl) increases the docking score, reflecting reduced ability of a molecule to fit inside the catalytic site of an enzyme. Indeed, previous studies have reported that larger leaving groups, such as propionyl, butyryl, (Z)-but-2-enyl, isobutyryl, 3-hydroxypropanyl, 3-methylbutanyl, 4-amino-4-oxobutanyl, and several other similar compounds are poor substrates for class I HDACs [39].


Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Bonomi R, Mukhopadhyay U, Shavrin A, Yeh HH, Majhi A, Dewage SW, Najjar A, Lu X, Cisneros GA, Tong WP, Alauddin MM, Liu RS, Mangner TJ, Turkman N, Gelovani JG - PLoS ONE (2015)

The structures of compounds and docking scores with HDAC8, a HDAC Class I enzyme.A lower docking score indicates higher affinity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526562&req=5

pone.0133512.g007: The structures of compounds and docking scores with HDAC8, a HDAC Class I enzyme.A lower docking score indicates higher affinity.
Mentions: Structural comparison of active sites of HDACs class I and IIa enzymes may explain the mechanism of selectivity of FAHA, DFAHA and TFAHA for HDACs class IIa. The major differences between HDACs class I (1, 2, 3 and 8) and HDACs class IIa (4, 5, 7 and 9) is the substitution of His976 (class IIa) for Tyr306 (class I) in the catalytic site. This change in amino acid residues in the catalytic site results in negligible intrinsic deacetylase activity but has two important structural consequences: the change in size of the active site, and the removal of a hydrogen bond donor site. Class I HDACs have a smaller catalytic cavity than class IIa enzymes, which explains why larger leaving groups do not fit in the catalytic site and are not cleaved by these enzymes. The docking results for HDAC 8 (class I) shown in Fig 7, demonstrate that increasing the size of the leaving group (acetyl < trifluoroacetyl) increases the docking score, reflecting reduced ability of a molecule to fit inside the catalytic site of an enzyme. Indeed, previous studies have reported that larger leaving groups, such as propionyl, butyryl, (Z)-but-2-enyl, isobutyryl, 3-hydroxypropanyl, 3-methylbutanyl, 4-amino-4-oxobutanyl, and several other similar compounds are poor substrates for class I HDACs [39].

Bottom Line: Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors.PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo.Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.

ABSTRACT
Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa-specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.

No MeSH data available.