Authors
Adi Suwandi, Jianwen Jin, Yichao Zhao, Ramesh Mudududdla, Yi Sing Gee, Girdhar Singh Deora, Yuxin Sun, Heping Wei, Fei Huang, Jin-Shu He, Amee J George, Stefan J Hermans, David J Leaver, Michael W Parker, Jonathan B Baell
Published in
Journal of medicinal chemistry. Volume 69. Issue 3. Pages 2082-2114. Feb 12, 2026. Epub Jan 29, 2026.
Abstract
All 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.
PMID:
41611522
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.
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