Takayoshi Suzuki

To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each containing a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compounds were synthesized by using click chemistry. Screening identified HDAC8-selective inhibitors including C149 (IC(50) = 0.070 μM), which was more potent than PCI-34058 (6) (IC(50) = 0.31 μM), a known HDA

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTLysine Demethylases InhibitorsTakayoshi Suzuki*†‡ and Naoki Miyata*§View Author Information† Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan‡ PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan§ Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-

Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington's disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we designed and prepared a series of 2-anilinobenzamide analogues. Enzyme assays using recombinant SIRT1 and SIRT2 revealed that 3'-phenethyloxy-2-anilinobenzamide analogues such as 33a and

A number of histone deacetylase (HDAC) inhibitors have been developed as anticancer agents and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA), Trichostatin A (TSA) and NVP-LAQ824. However, hydroxamic acids have been associated with poor pharmacokinetics and severe toxicity. In addition, although isozyme-selective HDAC inhibitors are considered useful not only as tools for probing the biology of an enzyme but as drugs with low toxicity, many of th

To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its pot

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

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

Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members have been identified and they can be divided into two categories, i.e., zinc-dependent enzymes (HDAC1-11) and NAD(+)-dependent enzymes (SIRT1-7). Some of the HDAC isoforms have important roles in cell functions, and are assoc

A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These results provide a basis for constructing new tools for probing the biology of GPR120 and for developing new candidate therapeutic agents.

Histone N(ε)-methyl lysine demethylases KDM2/7 have been identified as potential targets for cancer therapies. On the basis of the crystal structure of KDM7B, we designed and prepared a series of hydroxamate analogues bearing an alkyl chain. Enzyme assays revealed that compound 9 potently inhibits KDM2A, KDM7A, and KDM7B, with IC50s of 6.8, 0.2, and 1.2 μM, respectively. While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiprolife

Drug drop off: Given that lysine-specific demethylase 1 (LSD1) could be potently and selectively inactivated by delivering phenylcyclopropylamine (PCPA), a weak and nonselective LSD1 inhibitor, directly to the enzyme's active site, a novel series of LSD1 inactivators (1) were designed. Biological and mechanistic studies indicate that 1 inhibits LSD1 potently and selectively. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materi

It all happened with a click: In a search for histone deacetylase (HDAC) inhibitors using in situ click chemistry, the first example of protein–Cu acceleration of the azide–alkyne cycloaddition reaction was uncovered. The copper center in the protein target HDAC8 catalyzed triazole formation between one azide–alkyne pair among 30 possibilities. These results provide a new route to HDAC inhibitors and a precedent for new types of protein-based catalysts for click chemistry. Detailed facts of impo

Sirtuin 2 (SIRT2), a member of the NAD⁺-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (<b>6</b>), we identified in this study the potent mechanism-based inactivator KPM-2 (<b>36</