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.Selective inhibitors of KAT6A and KAT6B inhibit MYST-catalysed histone acetylation, induce cell cycle exit and cellular senescence without causing DNA damage, and arrest lymphoma progression in mouse models.

中文翻译：

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组蛋白乙酰转移酶抑制剂 KAT6A/B 诱导衰老并阻止肿瘤生长

赖氨酸乙酰转移酶 (KAT) 对组蛋白的乙酰化对于染色质组织和功能至关重要 1。在编码 MYST 家族 KAT (KAT5–KAT8) 的基因中有致癌基因 KAT6A（也称为 MOZ）和 KAT6B（也称为 MORF 和 QKF）2,3。KAT6A 在正常造血干细胞 4-6 中具有重要作用，并且是复发性染色体易位的目标，导致急性髓系白血病 7,8。类似地，KAT6B 中的染色体易位已在多种癌症中得到鉴定。KAT6A 通过调节 CDKN2A 基因座 9,10 的抑制因子来抑制细胞衰老，该功能需要其 KAT 活性 10。KAT6A 的一个等位基因的缺失将 MYC 诱导的淋巴瘤小鼠的中位生存期从 105 天延长到 413 天11。这些发现表明抑制 KAT6A 和 KAT6B 可能对癌症有治疗作用。在这里，我们提出了 KAT6A 和 KAT6B 的高效选择性抑制剂，表示为 WM-8014 和 WM-1119。生化和结构研究表明，这些化合物是乙酰辅酶 A 的可逆竞争者并抑制 MYST 催化的组蛋白乙酰化。WM-8014 和 WM-1119 在不引起 DNA 损伤的情况下诱导细胞周期退出和细胞衰老。衰老是 INK4A/ARF 依赖性的，并伴随着基因表达的变化，这是 KAT6A 功能丧失的典型特征。WM-8014 在体外和斑马鱼肝细胞癌模型中增强致癌基因诱导的衰老。WM-1119 提高了生物利用度，可阻止小鼠淋巴瘤的进展。