Regulation of gene expression is implicated in many disease processes, both as a response to a disease state and as the causative event. Aberrant gene expression is particularly associated with tumour formation. Chromatin structure is intimately related to the level of gene expression and highly abnormal chromatin landscape is typical of cancer. Accordingly, chromosomal translocations involving genes encoding chromatin-modifying proteins are prevalent among the most aggressive cancers. Post-translational modification of histones, especially lysine acetylation, which is associated with gene activation, plays a critical role in regulating the overall structure of chromatin and the level of gene expression. The five membered MYST proteins comprise the largest family of histone acetyltransferases. In particular KAT6A and KAT6B are the target of disease-causing chromosomal translocations and amplifications in cancer.
We have developed highly specific, potent inhibitors of KAT6 and shown that these are reversible competitors of acetyl coenzyme A and inhibit histone acetylation.1 These inhibitors induce cell cycle exit and cellular senescence without causing DNA damage in a CDKN2A dependent fashion. In model systems we have shown that they potentiate oncogene induced senescence. In particular, our most active compound arrests the progression of MYC driven lymphoma in mice.