A KAT6A/B Inhibitor Induces Senescence to Suppress Tumorigenesis

The closely related lysine acetyltransferases KAT6A and KAT6B acetylate histones to regulate chromatin organization and function, and are also the target of recurrent chromosomal translocations in cancer. KAT6A is recurrently translocated in acute myeloid leukemia (AML) and plays an essential role in normal hematopoietic stem cells, and loss of heterozygosity extends survival in mice with MYC-induced lymphoma. Similarly, KAT6B is recurrently translocated in a variety of tumor types. These findings provide a rationale for the development of KAT6A/B inhibitors for cancer therapy. To identify KAT6A inhibitors, Baell and colleagues performed a screen of 243,000 diverse small-molecule compounds, which identified a competitive KAT6A inhibitor that, after optimization, yielded WM-8014. WM-8014 inhibited both KAT6A and KAT6B, with much less activity against other KAT proteins. The crystal structure of a modified histone acetyltransferase domain in complex with WM-8014 demonstrated that the compound is a reversible competitor of acetyl coenzyme A. In mouse embryonic fibroblasts, WM-8014 induced cellular senescence with a corresponding upregulation of Cdkn2a, and downregulation of the KAT6A target gene Cdc6. WM-8014 reduced acetylation of H3K9 at KAT6 target genes specifically, and reduced acetylation of H3K14 (mediated by KAT7) throughout the genome, demonstrating on-target effects on histone acetylation. WM-8014 resulted in gene expression changes similar to KAT6A loss, including downregulation of E2f2, Ezh2, and Melk. WM-8014 enhanced oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. A WM-8014 derivative more suitable for in vivo use, WM-1119, suppressed the growth of lymphoma in mice. In addition to developing a novel class of inhibitors targeting histone acetylation, these findings suggest that inhibiting KAT6A/B may induce senescence and suppress tumor progression.

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;560:253–7.

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