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 & 32 others 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

Research output: Contribution to journalLetterResearchpeer-review

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.

Original languageEnglish
Pages (from-to)253-257
Number of pages5
JournalNature
Volume560
Issue number7717
DOIs
Publication statusPublished - 9 Aug 2018

Cite this

Baell, J. B., Leaver, D. J., Hermans, S. J., Kelly, G. L., Brennan, M. S., Downer, N. L., ... Thomas, T. (2018). Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature, 560(7717), 253-257. https://doi.org/10.1038/s41586-018-0387-5
Baell, Jonathan B. ; Leaver, David J. ; Hermans, Stefan J. ; Kelly, Gemma L. ; Brennan, Margs S. ; Downer, Natalie L. ; Nguyen, Nghi ; Wichmann, Johannes ; McRae, Helen M. ; Yang, Yuqing ; Cleary, Ben ; Lagiakos, H. Rachel ; Mieruszynski, Stephen ; Pacini, Guido ; Vanyai, Hannah K. ; Bergamasco, Maria I. ; May, Rose E. ; Davey, Bethany K. ; Morgan, Kimberly J. ; Sealey, Andrew J. ; Wang, Beinan ; Zamudio, Natasha ; Wilcox, Stephen ; Garnham, Alexandra L. ; Sheikh, Bilal N. ; Aubrey, Brandon J. ; Doggett, Karen ; Chung, Matthew C. ; de Silva, Melanie ; Bentley, John ; Pilling, Pat ; Hattarki, Meghan ; Dolezal, Olan ; Dennis, Matthew L. ; Falk, Hendrik ; Ren, Bin ; Charman, Susan A. ; White, Karen L. ; Rautela, Jai ; Newbold, Andrea ; Hawkins, Edwin D. ; Johnstone, Ricky W. ; Huntington, Nicholas D. ; Peat, Thomas S. ; Heath, Joan K. ; Strasser, Andreas ; Parker, Michael W. ; Smyth, Gordon K. ; Street, Ian P. ; Monahan, Brendon J. ; Voss, Anne K. ; Thomas, Tim. / Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. In: Nature. 2018 ; Vol. 560, No. 7717. pp. 253-257.
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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–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.",
author = "Baell, {Jonathan B.} and Leaver, {David J.} 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 Yuqing Yang and Ben 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",
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Baell, JB, Leaver, DJ, 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, no. 7717, pp. 253-257. https://doi.org/10.1038/s41586-018-0387-5

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. / Baell, Jonathan B.; Leaver, David J.; Hermans, Stefan J.; Kelly, Gemma L.; Brennan, Margs S.; Downer, Natalie L.; Nguyen, Nghi; Wichmann, Johannes; McRae, Helen M.; Yang, Yuqing; Cleary, Ben; Lagiakos, H. Rachel; Mieruszynski, Stephen; Pacini, Guido; Vanyai, Hannah K.; Bergamasco, Maria I.; May, Rose E.; Davey, Bethany K.; Morgan, Kimberly J.; Sealey, Andrew J.; Wang, Beinan; Zamudio, Natasha; Wilcox, Stephen; Garnham, Alexandra L.; Sheikh, Bilal N.; Aubrey, Brandon J.; Doggett, Karen; Chung, Matthew C.; de Silva, Melanie; Bentley, John; Pilling, Pat; Hattarki, Meghan; Dolezal, Olan; Dennis, Matthew L.; Falk, Hendrik; Ren, Bin; Charman, Susan A.; White, Karen L.; Rautela, Jai; Newbold, Andrea; Hawkins, Edwin D.; Johnstone, Ricky W.; Huntington, Nicholas D.; Peat, Thomas S.; Heath, Joan K.; Strasser, Andreas; Parker, Michael W.; Smyth, Gordon K.; Street, Ian P.; Monahan, Brendon J.; Voss, Anne K.; Thomas, Tim.

In: Nature, Vol. 560, No. 7717, 09.08.2018, p. 253-257.

Research output: Contribution to journalLetterResearchpeer-review

TY - JOUR

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

AU - Baell, Jonathan B.

AU - Leaver, David J.

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, Yuqing

AU - Cleary, Ben

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 - 2018/8/9

Y1 - 2018/8/9

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 cells4–6 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 cells4–6 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.

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U2 - 10.1038/s41586-018-0387-5

DO - 10.1038/s41586-018-0387-5

M3 - Letter

VL - 560

SP - 253

EP - 257

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7717

ER -

Baell JB, Leaver DJ, Hermans SJ, Kelly GL, Brennan MS, Downer NL et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018 Aug 9;560(7717):253-257. https://doi.org/10.1038/s41586-018-0387-5