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

Jonathan B. Baell; David Leaver; Stefan J. Hermans; Gemma L. Kelly; Margs S Brennan; Natalie L. Downer; Nghi Nguyen; Johannes Wichmann; Helen M. McRae; Yuquing Yang; Benjamin 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 de 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; Tim Thomas

doi:10.1038/s41586-018-0387-5

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

Jonathan B. Baell
, David Leaver
, Stefan J. Hermans
, Gemma L. Kelly
, Margs S Brennan
, Natalie L. Downer
, Nghi Nguyen
, Johannes Wichmann
, Helen M. McRae
, Yuquing Yang
, Benjamin 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 de 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, Tim Thomas

Monash Institute of Pharmaceutical Sciences
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
The University of Melbourne
Tsinghua University
CSIRO
Peter Maccallum Cancer Centre
Nanjing Tech University
Monash Institute of Pharmaceutical Sciences
Monash University
St. Vincent's Institute of Medical Research
Cancer Therapeutics CRC
Monash University, Centre for Drug Candidate Optimisation

Research output: Contribution to journal › Article › peer-review

272 Citations (Scopus)

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 cells^4,5,6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia^7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers⁸. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus^9,10, 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.

Original language	English
Pages (from-to)	253-257
Number of pages	21
Journal	Nature
Volume	560
DOIs	https://doi.org/10.1038/s41586-018-0387-5
Publication status	Published - 19 Aug 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41586-018-0387-5

272 Citations
1 Abstract
1 Presentation only

Drugging the undruggable — KATing away at cancer
Leaver, D., 2025, p. 52. 1 p.
Research output: Other contribution to conference › Abstract › peer-review
Inducing cellular senescence and arresting tumor growth with KAT6A/B inhibitors
Leaver, D., Baell, J. B., Hermans, S. J., Kelly, G. L., Brennan, M. S., Nguyen, N., Cleary, B., Lagiakos, H. R., Sheikh, B. N., Chung, M. C., Falk, H., Rautela, J., Newbold, A., Hawkins, E. D., Johnstone, R. W., Huntington, N. D., Strasser, A., Voss, A. K. & Thomas, T., 2018.
Research output: Other contribution to conference › Presentation only › peer-review

Cite this

Baell, J. B., Leaver, D., Hermans, S. J., Kelly, G. L., Brennan, M. S., Downer, N. L., Nguyen, N., Wichmann, J., McRae, H. M., Yang, Y., Cleary, B., Lagiakos, H. R., Mieruszynski, S., Pacini, G., Vanyai, H. K., Bergamasco, M. I., May, R. E., Davey, B. K., Morgan, K. J., ... Thomas, T. (2018). Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature, 560, 253-257. https://doi.org/10.1038/s41586-018-0387-5

@article{9540f056373049c3a1239a81d4fc0222,

title = "Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth",

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{\textendash}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 cells4,5,6 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.",

author = "Baell, \{Jonathan B.\} and David Leaver and Hermans, \{Stefan J.\} and Kelly, \{Gemma L.\} and Brennan, \{Margs S\} and Downer, \{Natalie L.\} and Nghi Nguyen and Johannes Wichmann and McRae, \{Helen M.\} and Yuquing Yang and Benjamin Cleary and Lagiakos, \{H. Rachel\} and Stephen Mieruszynski and Guido Pacini and Vanyai, \{Hannah K.\} and Bergamasco, \{Maria I.\} and May, \{Rose E.\} and Davey, \{Bethany K.\} and Morgan, \{Kimberly J.\} and Sealey, \{Andrew J.\} and Beinan Wang and Natasha Zamudio and Stephen Wilcox and Garnham, \{Alexandra L.\} and Sheikh, \{Bilal N.\} and Aubrey, \{Brandon J.\} and Karen Doggett and Chung, \{Matthew C.\} and \{de Silva\}, Melanie and John Bentley and Pat Pilling and Meghan Hattarki and Olan Dolezal and Dennis, \{Matthew L.\} and Hendrik Falk and Bin Ren and Charman, \{Susan A.\} and White, \{Karen L.\} and Jai Rautela and Andrea Newbold and Hawkins, \{Edwin D.\} and Johnstone, \{Ricky W.\} and Huntington, \{Nicholas D.\} and Peat, \{Thomas S.\} and Heath, \{Joan K.\} and Andreas Strasser and Parker, \{Michael W.\} and Smyth, \{Gordon K\} and Street, \{Ian P.\} and Monahan, \{Brendon J.\} and Voss, \{Anne K.\} and Tim Thomas",

year = "2018",

month = aug,

day = "19",

doi = "10.1038/s41586-018-0387-5",

language = "English",

volume = "560",

pages = "253--257",

journal = "Nature",

issn = "1476-4687",

publisher = "Nature Research",

}

Baell, JB, Leaver, D, Hermans, SJ, Kelly, GL, Brennan, MS, Downer, NL, Nguyen, N, Wichmann, J, McRae, HM, Yang, Y, Cleary, B, Lagiakos, HR, Mieruszynski, S, Pacini, G, Vanyai, HK, Bergamasco, MI, May, RE, Davey, BK, Morgan, KJ, Sealey, AJ, Wang, B, Zamudio, N, Wilcox, S, Garnham, AL, Sheikh, BN, Aubrey, BJ, Doggett, K, Chung, MC, de Silva, M, Bentley, J, Pilling, P, Hattarki, M, Dolezal, O, Dennis, ML, Falk, H, Ren, B, Charman, SA, White, KL, Rautela, J, Newbold, A, Hawkins, ED, Johnstone, RW, Huntington, ND, Peat, TS, Heath, JK, Strasser, A, Parker, MW, Smyth, GK, Street, IP, Monahan, BJ, Voss, AK & Thomas, T 2018, 'Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth', Nature, vol. 560, pp. 253-257. https://doi.org/10.1038/s41586-018-0387-5

TY - JOUR

T1 - Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

AU - Baell, Jonathan B.

AU - Leaver, David

AU - Hermans, Stefan J.

AU - Kelly, Gemma L.

AU - Brennan, Margs S

AU - Downer, Natalie L.

AU - Nguyen, Nghi

AU - Wichmann, Johannes

AU - McRae, Helen M.

AU - Yang, Yuquing

AU - Cleary, Benjamin

AU - Lagiakos, H. Rachel

AU - Mieruszynski, Stephen

AU - Pacini, Guido

AU - Vanyai, Hannah K.

AU - Bergamasco, Maria I.

AU - May, Rose E.

AU - Davey, Bethany K.

AU - Morgan, Kimberly J.

AU - Sealey, Andrew J.

AU - Wang, Beinan

AU - Zamudio, Natasha

AU - Wilcox, Stephen

AU - Garnham, Alexandra L.

AU - Sheikh, Bilal N.

AU - Aubrey, Brandon J.

AU - Doggett, Karen

AU - Chung, Matthew C.

AU - de Silva, Melanie

AU - Bentley, John

AU - Pilling, Pat

AU - Hattarki, Meghan

AU - Dolezal, Olan

AU - Dennis, Matthew L.

AU - Falk, Hendrik

AU - Ren, Bin

AU - Charman, Susan A.

AU - White, Karen L.

AU - Rautela, Jai

AU - Newbold, Andrea

AU - Hawkins, Edwin D.

AU - Johnstone, Ricky W.

AU - Huntington, Nicholas D.

AU - Peat, Thomas S.

AU - Heath, Joan K.

AU - Strasser, Andreas

AU - Parker, Michael W.

AU - Smyth, Gordon K

AU - Street, Ian P.

AU - Monahan, Brendon J.

AU - Voss, Anne K.

AU - Thomas, Tim

PY - 2018/8/19

Y1 - 2018/8/19

N2 - 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 cells4,5,6 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.

AB - 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 cells4,5,6 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.

U2 - 10.1038/s41586-018-0387-5

DO - 10.1038/s41586-018-0387-5

M3 - Article

C2 - 30069049

SN - 1476-4687

VL - 560

SP - 253

EP - 257

JO - Nature

JF - Nature

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Research output

Drugging the undruggable — KATing away at cancer

Inducing cellular senescence and arresting tumor growth with KAT6A/B inhibitors

Cite this