2. Academic Validation
  3. Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor

Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor

  • J Med Chem. 2024 Nov 14;67(21):19282-19303. doi: 10.1021/acs.jmedchem.4c01709.
Antonius Ter Laak 1,  Roman C Hillig 1,  Steven J Ferrara 2,  Daniel Korr 1,  Naomi Barak 1,  Philip Lienau 1,  Simon Herbert 1,  Amaury Ernesto Fernández-Montalván 1,  Roland Neuhaus 1,  Mátyás Gorjánácz 1,  Vera Puetter 1,  Volker Badock 1,  Wilhelm Bone 1,  Craig Strathdee 2,  Franziska Siegel 1,  Christoph Schatz 1,  Katrin Nowak-Reppel 1,  Olaf Doehr 1,  Stefan Gradl 1,  Ingo V Hartung 1,  Matthew Meyerson 2,  Léa Bouché 1
Affiliations

Affiliations

  • 1 Bayer AG, Pharmaceuticals, Research and Development, Müllerstrasse 178, Berlin 13353, Germany.
  • 2 Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, 415 Main St., Cambridge, Massachusetts 02142, United States.
PMID: 39450890 DOI: 10.1021/acs.jmedchem.4c01709
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.

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