Identification of a small molecule SIRT2 inhibitor with selective tumor cytotoxicity

被引：71

作者：

Zhang, Yingjia ^{[1
]}

Au, Qingyan ^{[1
]}

Zhang, Menghua ^{[1
]}

Barber, Jack R. ^{[1
]}

Ng, Shi Chung ^{[1
]}

Zhang, Bin ^{[1
]}

机构：

[1] CytRx Corp, Dept Biol, San Diego, CA 92109 USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 386卷 / 04期

关键词：

Sirtuins; SIRT2; Inhibitor; Cancer; Small molecule; AC-93253; DEPENDENT DEACETYLASE; TUBULIN DEACETYLASE; THERAPEUTIC TARGETS; CELL-CYCLE; SIRTUINS; TYPE-2; P53; DISEASES; SURAMIN; ANALOGS;

D O I：

10.1016/j.bbrc.2009.06.113

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

As a member of the class III histone deacetylases, Sirtuin-2 (SIRT2) is critical in cell cycle regulation which makes it a potential target for cancer therapeutics. In this study, we identified a novel SIRT2 inhibitor, AC-93253, with IC50 of 6 mu M in vitro. The compound is selective, inhibiting SIRT2 7.5- and 4-fold more potently than the closely related SIRT1 and SIRT3, respectively. AC-93253 significantly enhanced acetylation of tubulin, p53, and histone H4, confirming SIRT2 and SIRT1 as its cellular targets. AC-93253 as a single agent exhibited submicromolar selective cytotoxicity towards all four tumor cell lines tested with a therapeutic window LIP to 200-fold, comparing to any of the three normal cell types tested. Results from high content analysis Suggested that AC-93253 significantly triggered apoptosis. Taken together, SIRT2 selective inhibitor AC-93253 may serve as a novel chemical scaffold for structure-activity relationship study and future lead development. (C) 2009 Elsevier Inc. All rights reserved.

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收藏

页码：729 / 733

页数：5

相关论文

共 28 条

[1] High-Content Image-Based Screening for Small-Molecule Chaperone Amplifiers in Heat Shock [J].

Au, Qingyan ;

Kanchanastit, Prim ;

Barber, Jack R. ;

Ng, Shi Chung ;

Zhang, Bin .

JOURNAL OF BIOMOLECULAR SCREENING, 2008, 13 (10) :953-959

[2] Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10 [J].

Bae, NS ;

Swanson, MJ ;

Vassilev, A ;

Howard, BH .

JOURNAL OF BIOCHEMISTRY, 2004, 135 (06) :695-700

[3] Identification of a small molecule inhibitor of Sir2p [J].

Bedalov, A ;

Gatbonton, T ;

Irvine, WP ;

Gottschling, DE ;

Simon, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :15113-15118

[4] Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase [J].

Brunet, A ;

Sweeney, LB ;

Sturgill, JF ;

Chua, KF ;

Greer, PL ;

Lin, YX ;

Tran, H ;

Ross, SE ;

Mostoslavsky, R ;

Cohen, HY ;

Hu, LS ;

Cheng, HL ;

Jedrychowski, MP ;

Gygi, SP ;

Sinclair, DA ;

Alt, FW ;

Greenberg, ME .

SCIENCE, 2004, 303 (5666) :2011-2015

[5] Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis [J].

Cohen, HY ;

Lavu, S ;

Bitterman, KJ ;

Hekking, B ;

Imahiyerobo, TA ;

Miller, C ;

Frye, R ;

Ploegh, H ;

Kessler, BM ;

Sinclair, DA .

MOLECULAR CELL, 2004, 13 (05) :627-638

[6] Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle [J].

Dryden, SC ;

Nahhas, FA ;

Nowak, JE ;

Goustin, AS ;

Tainsky, MA .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (09) :3173-3185

[7] Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening [J].

Grozinger, CM ;

Chao, ED ;

Blackwell, HE ;

Moazed, D ;

Schreiber, SL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38837-38843

[8] Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes [J].

Heltweg, B ;

Gatbonton, T ;

Schuler, AD ;

Posakony, J ;

Li, HZ ;

Goehle, S ;

Kollipara, R ;

DePinho, RA ;

Gu, YS ;

Simon, JA ;

Bedalov, A .

CANCER RESEARCH, 2006, 66 (08) :4368-4377

[9] HDAC6 is a microtubule-associated deacetylase [J].

Hubbert, C ;

Guardiola, A ;

Shao, R ;

Kawaguchi, Y ;

Ito, A ;

Nixon, A ;

Yoshida, M ;

Wang, XF ;

Yao, TP .

NATURE, 2002, 417 (6887) :455-458

[10] SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress [J].

Inoue, T. ;

Hiratsuka, M. ;

Osaki, M. ;

Yamada, H. ;

Kishimoto, I. ;

Yamaguchi, S. ;

Nakano, S. ;

Katoh, M. ;

Ito, H. ;

Oshimura, M. .

ONCOGENE, 2007, 26 (07) :945-957