Journal of medicinal chemistry · 2024
Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor.
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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
Аннотация
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.