Biological Activity and Structural Biology of Current KAT6A Inhibitor Chemotypes
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 <i>in vivo</i> 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 <i>in vivo</i> activity, pharmacokinetics, and toxicology profiles of these inhibitors.
Authors
- Michael W. Parker (ORCID: https://orcid.org/0000-0002-3101-1138)
- Jianwen Jin (ORCID: https://orcid.org/0000-0001-5335-5890)
- Amee J. George (ORCID: https://orcid.org/0000-0002-0265-4476)
- Yu Sun (ORCID: https://orcid.org/0000-0003-0863-2769)
- Jonathan B. Baell (ORCID: https://orcid.org/0000-0003-2114-8242)
- Yi Sing Gee (ORCID: https://orcid.org/0000-0002-2707-6270)
- Adi Suwandi (ORCID: https://orcid.org/0000-0002-5917-7228)
- Fei Huang (ORCID: https://orcid.org/0000-0001-9769-4798)
- Jin-Shu He (ORCID: https://orcid.org/0000-0001-7354-0233)
- Yichao Zhao (ORCID: https://orcid.org/0000-0001-8784-5361)
- S.J. Hermans (ORCID: https://orcid.org/0000-0002-2513-5054)
- Ramesh Mudududdla
- Girdhar Singh Deora
- Heping Wei
- David J. Leaver
Institutions
- Australian National University (AU)
- Biotechnology Institute (US)
- Nanjing Tech University (CN)
- Charles Sturt University (AU)
- The University of Melbourne (AU)
- Curtin University (AU)
- Discovery Centre (CA)
- Australian Regenerative Medicine Institute (AU)
- Rational (Germany) (DE)
- Institute of Medicinal Plant Development (CN)
- AGRF Ltd (AU)
- Chemical Synthesis Lab (SG)
- Monash University (AU)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01426
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00