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New KAT6 inhibitors induce senescence and arrest cancer growth.
Synthetic and Systems Biotechnology 2018 December
Lysine acetyltransferases (KATs) catalyze lysine acetylation, a reversible protein modification implicated in a wide variety of disease states. Histone acetyltransferases (HATs) comprise a KAT sub-class that acetylate specific lysines in histones, hence playing an important role in the regulation of chromatin organization and function. HATs are critical regulators of signaling in many diseases, including cancer. KAT6A (also known as monocytic leukemia zinc finger protein, MOZ) and KAT6B (also known as MORF and QKF) belong to the MYST family of HATs, that comprise KAT5-KAT8. They are the targets of chromosomal translocations identified in acute myeloid leukaemia and various cancers. It seems logical therefore that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Baell et al. discovered a new class of anti-cancer drug that can put cancer cells into a permanent sleep or senescence, using high-throughput screening followed by medicinal chemistry optimization, in-cell assays, biochemical assessment of target engagement, and tumour models in mice and fish. This research showed promise in arresting tumour growth in pre-clinical models of blood and liver cancers as well as delaying or stopping relapse without damaging the cells' DNA or some harmful side-effects caused by chemotherapy and radiotherapy.
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