9ooa
Crystal structure of MYST acetyltransferase domain in complex with inhibitor 7
Structural highlights
FunctionKAT8_HUMAN Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex.[1] [2] [3] Publication Abstract from PubMedAll lysine acetyltransferases (KATs) modulate biological outcomes through the acetylation of lysine side-chain amino groups facilitated by acetyl coenzyme A (AcCoA). KAT6A belongs to the class of MYST domain histone acetyltransferases (HATs), which had been regarded as undruggable. The first on-target KAT6A inhibitors with in vivo activity were reported in 2018, catalyzing intense industry interest in this enzyme as an oncology target. In this study, we experimentally evaluated representative KAT6A inhibitor chemotypes through resynthesis and comparative biochemical assays, cellular assays, and structural biology. We outline the recent history of each KAT6A inhibitor chemotype discovery, including SAR for potency, selectivity, and cellular activity. We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors. Biological Activity and Structural Biology of Current KAT6A Inhibitor Chemotypes.,Suwandi A, Jin J, Zhao Y, Mudududdla R, Gee YS, Deora GS, Sun Y, Wei H, Huang F, He JS, George AJ, Hermans SJ, Leaver DJ, Parker MW, Baell JB J Med Chem. 2026 Jan 29. doi: 10.1021/acs.jmedchem.5c01426. PMID:41611522[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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