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Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.

ABSTRACT: SIRT2 is a member of the human sirtuin family of proteins and possesses NAD+-dependent lysine deacetylase/deacylase activity. SIRT2 has been implicated in carcinogenesis in various cancers including leukaemia and is considered an attractive target for cancer therapy. Here, we identified NPD11033, a selective small-molecule SIRT2 inhibitor, by a high-throughput screen using the RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins and zinc-dependent deacetylases. Crystallographic analysis revealed a unique mode of action, in which NPD11033 creates a hydrophobic cavity behind the substrate-binding pocket after a conformational change of the Zn-binding small domain of SIRT2. Furthermore, it forms a hydrogen bond to the active site histidine residue. In addition, NPD11033 inhibited cell growth of human pancreatic cancer PANC-1 cells with a concomitant increase in the acetylation of eukaryotic translation initiation factor 5A, a physiological substrate of SIRT2. Importantly, NPD11033 failed to inhibit defatty-acylase activity of SIRT2, despite its potent inhibitory effect on its deacetylase activity. Thus, NPD11033 will serve as a useful tool for both developing novel anti-cancer agents and elucidating the role of SIRT2 in various cellular biological processes.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

SUBMITTER: Kudo N

PROVIDER: S-EPMC5915714 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.

Kudo Norio N Ito Akihiro A Arata Mayumi M Nakata Akiko A Yoshida Minoru M

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20180601 1748

SIRT2 is a member of the human sirtuin family of proteins and possesses NAD<sup>+</sup>-dependent lysine deacetylase/deacylase activity. SIRT2 has been implicated in carcinogenesis in various cancers including leukaemia and is considered an attractive target for cancer therapy. Here, we identified NPD11033, a selective small-molecule SIRT2 inhibitor, by a high-throughput screen using the RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins and zinc-dependent deacet ...[more]

PMID: 29685974

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Project description:BackgroundSirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide+-dependent deacylases, which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Downregulation of SIRT2 using siRNA causes apoptosis of HeLa cells. Therefore, selective inhibitors of SIRT2 are candidate therapeutic agents for cancer. Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy that has a poor prognosis and develops after long-term infection with human T-cell leukemia virus (HTLV)-1. Sirtuin 1 inhibition has been shown to induce apoptosis and autophagy in HTLV-1-infected cell lines, whereas the effects of SIRT2 inhibition alone have not been elucidated.MethodsWe assessed the efficacy of our small molecule selective SIRT2 inhibitors NCO-90/141 to induce leukemic cell death. Cell viability was examined using the cell proliferation reagent Cell Count Reagent SF. Apoptotic cells were detected by annexin V-FITC and terminal deoxynucleotidyl transferase dUTP nick end labeling assays by flow cytometry. Caspase activity was detected using an APOPCYTO Intracellular Caspase Activity Detection Kit. The presence of autophagic vacuoles was assessed using a Cyto-ID Autophagy Detection Kit.ResultsOur novel small molecule SIRT2-specific inhibitors NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T-cells. NCO-90/141 induced apoptosis via caspase activation and mitochondrial superoxide generation in leukemic cell lines. However, a caspase inhibitor did not prevent this caspase-associated cell death. Interestingly, NCO-90/141 increased the LC3-II level together with autophagosome accumulation, indicating autophagic cell death. Thus, NCO-90/141 simultaneously caused apoptosis and autophagy.ConclusionsThese results suggest that NCO-90/141 are highly effective against leukemic cells in caspase-dependent or -independent manners via autophagy, and they may have a novel therapeutic potential for treatment of leukemias including ATL.

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Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.

Publications

Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.

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