Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor
Year: 2024
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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.
Source: Journal of Medicinal Chemistry
Authors: 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 Gradl, Ingo V. Hartung, Matthew Meyerson, Léa Bouché
Institutions: Bayer (Germany), Broad Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Bayer, Broad Institute
OpenAlex ID: W4403767980