Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran <i>In Vivo</i>-Active KAT6AB Inhibitor
KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12-15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 (<b>29</b>), was successfully validated in an <i>in vivo</i> proof-of-concept study.
Authors
- Ingo V. Hartung (ORCID: https://orcid.org/0000-0001-8750-679X)
- Stefan Gradl
- Christoph A. Schatz (ORCID: https://orcid.org/0000-0001-8028-2631)
- Katrin Nowak‐Reppel
- Naomi Barak (ORCID: https://orcid.org/0000-0002-8166-9616)
- Volker Badock (ORCID: https://orcid.org/0000-0002-5437-3916)
- Léa Bouché (ORCID: https://orcid.org/0000-0001-8523-812X)
- Wilhelm Bone
- Simon A. Herbert
- Roland Neuhaus
- Vera Puetter
- Antonius ter Laak (ORCID: https://orcid.org/0000-0003-1820-002X)
- Steven Ferrara
- R.C. Hillig (ORCID: https://orcid.org/0000-0001-6267-7250)
- Franziska Siegel
- Matthew Meyerson (ORCID: https://orcid.org/0000-0002-9133-8108)
- Craig A. Strathdee
- Mátyás Gorjánácz (ORCID: https://orcid.org/0000-0002-8398-410X)
- Amaury E. Fernández‐Montalván (ORCID: https://orcid.org/0000-0001-9156-0000)
- Philip Lienau (ORCID: https://orcid.org/0000-0002-6048-4559)
- Olaf Doehr
- Daniel Korr
Institutions
- Broad Institute (US)
- Bayer (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01709
- Citations
- 8
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Bayer
- Broad Institute