Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate

被引：102

作者：

Suzuki, Takayoshi

Kouketsu, Akiyasu

Itoh, Yukihiro

Hisakawa, Shinya

Maeda, Satoko

Yoshida, Minoru

Nakagawa, Hidehiko

Miyata, Naoki

机构：

[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Mizuho Ku, Nagoya, Aichi 4678603, Japan

[2] RIKEN, Saitama 3510198, Japan

[3] CREST Res Project, Japan Sci & Technol Agcy, Saitama 332001, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 16期

关键词：

D O I：

10.1021/jm060554y

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

To find novel histone deacetylase 6 (HDAC6)-selective inhibitors and clarify the structural requirements for HDAC6-selective inhibition, we prepared thiolate analogues designed based on the structure of an HDAC6-selective substrate and evaluated the histone/ alpha-tubulin acetylation selectivity by Western blot analysis. Aliphatic compounds 17b-20b selectively caused alpha-tubulin acetylation over histone H4 acetylation. In enzyme assays using HDAC1, HDAC4, and HDAC6, compounds 17a-19a exhibited HDAC6-selective inhibition over HDAC1 and HDAC4.

引用

收藏

页码：4809 / 4812

页数：4

相关论文

共 37 条

[1]

Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 - A novel basis for antileukemia activity of histone deacetylase inhibitors [J].

Bali, P ;

Pranpat, M ;

Bradner, J ;

Balasis, M ;

Fiskus, W ;

Guo, F ;

Rocha, K ;

Kumaraswamy, S ;

Boyapalle, S ;

Atadja, P ;

Seto, E ;

Bhalla, K .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (29) :26729-26734

[2]

Epigenetics - An epicenter of gene regulation: Histones and histone-modifying enzymes [J].

Biel, M ;

Wascholowski, V ;

Giannis, A .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2005, 44 (21) :3186-3216

[3]

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin [J].

Furumai, R ;

Komatsu, Y ;

Nishino, N ;

Khochbin, S ;

Yoshida, M ;

Horinouchi, S .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (01) :87-92

[4]

Differential protein acetylation induced by novel histone deacetylase inhibitors [J].

Glaser, KB ;

Li, J ;

Pease, LJ ;

Staver, MJ ;

Marcotte, PA ;

Guo, J ;

Frey, RR ;

Garland, RB ;

Heyman, HR ;

Wada, CK ;

Vasudevan, A ;

Michaelides, MR ;

Davidsen, SK ;

Curtin, ML .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 325 (03) :683-690

[5]

Deacetylase enzymes: biological functions and the use of small-molecule inhibitors [J].

Grozinger, CM ;

Schreiber, SL .

CHEMISTRY & BIOLOGY, 2002, 9 (01) :3-16

[6]

Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays [J].

Haggarty, SJ ;

Koeller, KM ;

Wong, JC ;

Butcher, RA ;

Schreiber, SL .

CHEMISTRY & BIOLOGY, 2003, 10 (05) :383-396

[7]

Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation [J].

Haggarty, SJ ;

Koeller, KM ;

Wong, JC ;

Grozinger, CM ;

Schreiber, SL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (08) :4389-4394

[8]

Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs [J].

Hassig, CA ;

Schreiber, SL .

CURRENT OPINION IN CHEMICAL BIOLOGY, 1997, 1 (03) :300-308

[9]

Subtype selective substrates for histone deacetylases [J].

Heltweg, B ;

Dequiedt, F ;

Marshall, BL ;

Branch, C ;

Yoshida, M ;

Nishino, N ;

Verdin, E ;

Jung, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (21) :5235-5243

[10]

Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma [J].

Hideshima, T ;

Bradner, JE ;

Wong, J ;

Chauhan, D ;

Richardson, P ;

Schreiber, SL ;

Anderson, KC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (24) :8567-8572

← 1 2 3 4 →