1. Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo -Active KAT6AB Inhibitor.
- Author
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Ter Laak A, Hillig RC, Ferrara SJ, Korr D, Barak N, Lienau P, Herbert S, Fernández-Montalván AE, Neuhaus R, Gorjánácz M, Puetter V, Badock V, Bone W, Strathdee C, Siegel F, Schatz C, Nowak-Reppel K, Doehr O, Gradl S, Hartung IV, Meyerson M, and Bouché L
- Subjects
- Humans, Structure-Activity Relationship, Animals, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Drug Discovery, Models, Molecular, Mice, Female, Cell Line, Tumor, Sulfonamides chemistry, Sulfonamides pharmacology, Sulfonamides chemical synthesis, Benzofurans chemistry, Benzofurans pharmacology, Histone Acetyltransferases antagonists & inhibitors, Histone Acetyltransferases metabolism
- Abstract
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.
- Published
- 2024
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