Article
Author: Lienau, Philip ; Hartung, Ingo V. ; Gradl, Stefan ; Ferrara, Steven J. ; Doehr, Olaf ; Gorjánácz, Mátyás ; Nowak-Reppel, Katrin ; Puetter, Vera ; Siegel, Franziska ; ter Laak, Antonius ; Schatz, Christoph ; Bone, Wilhelm ; Fernández-Montalván, Amaury Ernesto ; Barak, Naomi ; Badock, Volker ; Bouché, Léa ; Herbert, Simon ; Strathdee, Craig ; Korr, Daniel ; Neuhaus, Roland ; Hillig, Roman C. ; Meyerson, Matthew
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.