Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

被引：220

作者：

Baell, Jonathan B. ^{[1
,2
]}

Leaver, David J. ^{[1
]}

Hermans, Stefan J. ^{[3
]}

Kelly, Gemma L. ^{[4
,5
]}

Brennan, Margs S. ^{[4
,5
]}

Downer, Natalie L. ^{[4
]}

Nguyen, Nghi ^{[1
]}

Wichmann, Johannes ^{[4
,5
]}

Mcrae, Helen M. ^{[4
,5
]}

Yang, Yuqing ^{[4
,5
]}

Cleary, Ben ^{[1
]}

Lagiakos, H. Rachel ^{[1
,6
]}

Mieruszynski, Stephen ^{[4
,5
]}

Pacini, Guido ^{[4
]}

Vanyai, Hannah K. ^{[4
,5
]}

Bergamasco, Maria I. ^{[4
,5
]}

May, Rose E. ^{[4
]}

Davey, Bethany K. ^{[4
,6
]}

Morgan, Kimberly J. ^{[4
,5
]}

Sealey, Andrew J. ^{[4
,5
]}

Wang, Beinan ^{[4
,5
,7
]}

Zamudio, Natasha ^{[4
,5
]}

Wilcox, Stephen ^{[4
,5
]}

Garnham, Alexandra L. ^{[4
,5
]}

Sheikh, Bilal N. ^{[4
,5
]}

Aubrey, Brandon J. ^{[4
,5
]}

Doggett, Karen ^{[4
,5
]}

Chung, Matthew C. ^{[3
]}

de Silva, Melanie ^{[4
,6
]}

Bentley, John ^{[8
]}

Pilling, Pat ^{[8
]}

Hattarki, Meghan ^{[8
]}

Dolezal, Olan ^{[8
]}

Dennis, Matthew L. ^{[8
]}

Falk, Hendrik ^{[4
,5
,6
]}

Ren, Bin ^{[8
]}

Charman, Susan A. ^{[9
]}

White, Karen L. ^{[9
]}

Rautela, Jai ^{[4
,5
]}

Newbold, Andrea ^{[4
,5
,10
]}

Hawkins, Edwin D. ^{[4
,5
]}

Johnstone, Ricky W. ^{[10
]}

Huntington, Nicholas D. ^{[4
,5
]}

Peat, Thomas S. ^{[8
]}

Heath, Joan K. ^{[4
,5
]}

Strasser, Andreas ^{[4
,5
]}

Parker, Michael W. ^{[3
,11
]}

Smyth, Gordon K. ^{[4
,12
]}

Street, Ian P. ^{[4
,5
,6
]}

Monahan, Brendon J. ^{[4
,5
,6
]}

机构：

[1] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem Theme, Parkville, Vic, Australia

[2] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing, Jiangsu, Peoples R China

[3] St Vincents Inst Med Res, ACRF Rational Drug Discovery Ctr, Fitzroy, Vic, Australia

[4] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia

[5] Univ Melbourne, Dept Med Biol, Parkville, Vic, Australia

[6] Canc Therapeut CRC, Parkville, Vic, Australia

[7] Tsinghua Univ, Sch Pharmaceut Sci, Beijing, Peoples R China

[8] CSIRO, Biomed Program, Parkville, Vic, Australia

[9] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic, Australia

[10] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[11] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Parkville, Vic, Australia

[12] Univ Melbourne, Dept Math & Stat, Parkville, Vic, Australia

来源：

NATURE | 2018年 / 560卷 / 7717期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

GENE-EXPRESSION; MOZ; PROTEIN; MAINTENANCE; PROGRESSION; KEGG; RAS; E2F; P53;

D O I：

10.1038/s41586-018-0387-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function(1). Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)(2,3). KAT6A has essential roles in normal haematopoietic stem cells(4-6) and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia(7,8). Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers(8). KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus(9,10), a function that requires its KAT activity(10). Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days(11). These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

引用

页码：253 / +

页数：17

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