6ba2
Crystal structure of MYST acetyltransferase domain in complex with inhibitorCrystal structure of MYST acetyltransferase domain in complex with inhibitor
Structural highlights
FunctionKAT8_HUMAN Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex.[1] [2] [3] Publication Abstract from PubMedAcetylation 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. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.,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 Nature. 2018 Aug;560(7717):253-257. doi: 10.1038/s41586-018-0387-5. Epub 2018 Aug, 1. PMID:30069049[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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