Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.

To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chemistry", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library...

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Autores principales:	Takayoshi Suzuki, Yuki Kasuya, Yukihiro Itoh, Yosuke Ota, Peng Zhan, Kaori Asamitsu, Hidehiko Nakagawa, Takashi Okamoto, Naoki Miyata
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d299e81947f04eb68108bf4f51d7a711
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spelling	oai:doaj.org-article:d299e81947f04eb68108bf4f51d7a7112021-11-18T07:37:32ZIdentification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.1932-620310.1371/journal.pone.0068669https://doaj.org/article/d299e81947f04eb68108bf4f51d7a7112013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23874714/?tool=EBIhttps://doaj.org/toc/1932-6203To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chemistry", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.Takayoshi SuzukiYuki KasuyaYukihiro ItohYosuke OtaPeng ZhanKaori AsamitsuHidehiko NakagawaTakashi OkamotoNaoki MiyataPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e68669 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takayoshi Suzuki Yuki Kasuya Yukihiro Itoh Yosuke Ota Peng Zhan Kaori Asamitsu Hidehiko Nakagawa Takashi Okamoto Naoki Miyata Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
description	To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chemistry", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.
format	article
author	Takayoshi Suzuki Yuki Kasuya Yukihiro Itoh Yosuke Ota Peng Zhan Kaori Asamitsu Hidehiko Nakagawa Takashi Okamoto Naoki Miyata
author_facet	Takayoshi Suzuki Yuki Kasuya Yukihiro Itoh Yosuke Ota Peng Zhan Kaori Asamitsu Hidehiko Nakagawa Takashi Okamoto Naoki Miyata
author_sort	Takayoshi Suzuki
title	Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
title_short	Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
title_full	Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
title_fullStr	Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
title_full_unstemmed	Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
title_sort	identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d299e81947f04eb68108bf4f51d7a711
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Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.

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