The addition of acetyl groups to the proteins that make up histones—the spools on which DNA is tightly wound in chromatin—plays a central role in managing the organization and function of the DNA packaging material. Some enzymes that catalyze that acetylation also play roles in cancer, but until recently researchers counted histone acetyltransferases among the undruggable targets. Now a team led by Jonathan B. Baell of Monash University and Anne K. Voss and Tim Thomas of the Walter & Eliza Hall Institute of Medical Research reports inhibitors of two members of the MYST family of histone acetyltransferases, KAT6A and KAT6B (Nature 2018, DOI: 10.1038/s41586-018-0387-5). The researchers identified a starting point by screening a 243,000-compound library and then used medicinal chemistry optimization to obtain two improved inhibitors, dubbed WM-8014 and WM-1119. Many cancer treatments damage DNA, but these inhibitors don’t. Instead, they induce cellular senescence without damaging DNA, in effect putting the cells to sleep. In zebrafish assays, the inhibitors shut down the cell cycle in liver cancer cells but did not affect the growth of normal liver cells. They also halted lymphoma tumor progression in mice. In both cases, WM-1119 was more potent and selective than WM-8014.