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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.
Afiliação
  • Baell JB; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Jonathan.Baell@monash.edu.
  • Leaver DJ; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China. Jonathan.Baell@monash.edu.
  • Hermans SJ; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Kelly GL; ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
  • Brennan MS; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Downer NL; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Nguyen N; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Wichmann J; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • McRae HM; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Yang Y; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Cleary B; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Lagiakos HR; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Mieruszynski S; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Pacini G; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Vanyai HK; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Bergamasco MI; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • May RE; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Davey BK; Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • Morgan KJ; Cancer Therapeutics CRC, Parkville, Victoria, Australia.
  • Sealey AJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Wang B; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Zamudio N; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Wilcox S; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Garnham AL; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Sheikh BN; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Aubrey BJ; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Doggett K; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Chung MC; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • de Silva M; Cancer Therapeutics CRC, Parkville, Victoria, Australia.
  • Bentley J; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Pilling P; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Hattarki M; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Dolezal O; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Dennis ML; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Falk H; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Ren B; School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • Charman SA; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • White KL; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Rautela J; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Newbold A; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Hawkins ED; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Johnstone RW; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Huntington ND; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Peat TS; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Heath JK; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Strasser A; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Parker MW; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
  • Smyth GK; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Street IP; ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
  • Monahan BJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria, Australia.
Nature ; 560(7717): 253-257, 2018 08.
Article em En | MEDLINE | ID: mdl-30069049
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonamidas / Benzenossulfonatos / Senescência Celular / Histona Acetiltransferases / Hidrazinas / Linfoma Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Nature Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonamidas / Benzenossulfonatos / Senescência Celular / Histona Acetiltransferases / Hidrazinas / Linfoma Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Nature Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Austrália