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.

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