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

Jonathan B. Baell (), David J. Leaver, Stefan J. Hermans, Gemma L. Kelly, Margs S. Brennan, Natalie L. Downer, Nghi Nguyen, Johannes Wichmann, Helen M. McRae, Yuqing Yang, Ben Cleary, H. Rachel Lagiakos, Stephen Mieruszynski, Guido Pacini, Hannah K. Vanyai, Maria I. Bergamasco, Rose E. May, Bethany K. Davey, Kimberly J. Morgan, Andrew J. Sealey, Beinan Wang, Natasha Zamudio, Stephen Wilcox, Alexandra L. Garnham, Bilal N. Sheikh, Brandon J. Aubrey, Karen Doggett, Matthew C. Chung, Melanie Silva, John Bentley, Pat Pilling, Meghan Hattarki, Olan Dolezal, Matthew L. Dennis, Hendrik Falk, Bin Ren, Susan A. Charman, Karen L. White, Jai Rautela, Andrea Newbold, Edwin D. Hawkins, Ricky W. Johnstone, Nicholas D. Huntington, Thomas S. Peat, Joan K. Heath, Andreas Strasser, Michael W. Parker, Gordon K. Smyth, Ian P. Street, Brendon J. Monahan, Anne K. Voss () and Tim Thomas ()
Additional contact information
Jonathan B. Baell: Monash University
David J. Leaver: Monash University
Stefan J. Hermans: St Vincent’s Institute of Medical Research
Gemma L. Kelly: The Walter and Eliza Hall Institute of Medical Research, Parkville
Margs S. Brennan: The Walter and Eliza Hall Institute of Medical Research, Parkville
Natalie L. Downer: The Walter and Eliza Hall Institute of Medical Research, Parkville
Nghi Nguyen: Monash University
Johannes Wichmann: The Walter and Eliza Hall Institute of Medical Research, Parkville
Helen M. McRae: The Walter and Eliza Hall Institute of Medical Research, Parkville
Yuqing Yang: The Walter and Eliza Hall Institute of Medical Research, Parkville
Ben Cleary: Monash University
H. Rachel Lagiakos: Monash University
Stephen Mieruszynski: The Walter and Eliza Hall Institute of Medical Research, Parkville
Guido Pacini: The Walter and Eliza Hall Institute of Medical Research, Parkville
Hannah K. Vanyai: The Walter and Eliza Hall Institute of Medical Research, Parkville
Maria I. Bergamasco: The Walter and Eliza Hall Institute of Medical Research, Parkville
Rose E. May: The Walter and Eliza Hall Institute of Medical Research, Parkville
Bethany K. Davey: The Walter and Eliza Hall Institute of Medical Research, Parkville
Kimberly J. Morgan: The Walter and Eliza Hall Institute of Medical Research, Parkville
Andrew J. Sealey: The Walter and Eliza Hall Institute of Medical Research, Parkville
Beinan Wang: The Walter and Eliza Hall Institute of Medical Research, Parkville
Natasha Zamudio: The Walter and Eliza Hall Institute of Medical Research, Parkville
Stephen Wilcox: The Walter and Eliza Hall Institute of Medical Research, Parkville
Alexandra L. Garnham: The Walter and Eliza Hall Institute of Medical Research, Parkville
Bilal N. Sheikh: The Walter and Eliza Hall Institute of Medical Research, Parkville
Brandon J. Aubrey: The Walter and Eliza Hall Institute of Medical Research, Parkville
Karen Doggett: The Walter and Eliza Hall Institute of Medical Research, Parkville
Matthew C. Chung: St Vincent’s Institute of Medical Research
Melanie Silva: The Walter and Eliza Hall Institute of Medical Research, Parkville
John Bentley: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Pat Pilling: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Meghan Hattarki: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Olan Dolezal: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Matthew L. Dennis: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Hendrik Falk: The Walter and Eliza Hall Institute of Medical Research, Parkville
Bin Ren: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Susan A. Charman: Monash University
Karen L. White: Monash University
Jai Rautela: The Walter and Eliza Hall Institute of Medical Research, Parkville
Andrea Newbold: The Peter MacCallum Cancer Centre
Edwin D. Hawkins: The Walter and Eliza Hall Institute of Medical Research, Parkville
Ricky W. Johnstone: The Peter MacCallum Cancer Centre
Nicholas D. Huntington: The Walter and Eliza Hall Institute of Medical Research, Parkville
Thomas S. Peat: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Biomedical Program
Joan K. Heath: The Walter and Eliza Hall Institute of Medical Research, Parkville
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research, Parkville
Michael W. Parker: St Vincent’s Institute of Medical Research
Gordon K. Smyth: The Walter and Eliza Hall Institute of Medical Research, Parkville
Ian P. Street: The Walter and Eliza Hall Institute of Medical Research, Parkville
Brendon J. Monahan: The Walter and Eliza Hall Institute of Medical Research, Parkville
Anne K. Voss: The Walter and Eliza Hall Institute of Medical Research, Parkville
Tim Thomas: The Walter and Eliza Hall Institute of Medical Research, Parkville

Nature, 2018, vol. 560, issue 7717, 253-257

Abstract: Abstract Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. 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 cells4–6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0387-5

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