Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor

• Published in: Journal of medicinal chemistry Vol. 67; no. 21; pp. 19282 - 19303
• Main Authors: ter Laak, Antonius, Hillig, Roman C., Ferrara, Steven J., Korr, Daniel, Barak, Naomi, Lienau, Philip, Herbert, Simon, Fernández-Montalván, Amaury Ernesto, Neuhaus, Roland, Gorjánácz, Mátyás, Puetter, Vera, Badock, Volker, Bone, Wilhelm, Strathdee, Craig, Siegel, Franziska, Schatz, Christoph, Nowak-Reppel, Katrin, Doehr, Olaf, Gradl, Stefan, Hartung, Ingo V., Meyerson, Matthew, Bouché, Léa
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.11.2024
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01709

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 (29), was successfully validated in an in vivo proof-of-concept study.