PO.ET09.02 · 实验与分子治疗

Development of a new class of KAT6A/B inhibitors with in vivo efficacy

编号 7064 展板 11 时间 4/22 09:00–12:00 区域 Section 12 主讲 Peter Staller

分会场 Epigenetic Modulators 2

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作者与单位

Antonius ter Laak¹, Roman Hillig², Steven Ferrara³, Daniel Korr², Peter Staller², Naomi Barak¹, Philip Lienau¹, Simon Herbert¹, Amaury Fernandez¹, Roland Neuhaus², Matyas Gorjanacz¹, Vera Puetter², Volker Badock², Wilhelm Bone², Craig Strathdee³, Franziska Siegel¹, Christoph Schatz¹, Nowak-Reppel Katrin², Olaf Doehr¹, Stefan Gradl¹, Ingo Hartung¹, Matthew Meyerson³, Lea Bouche¹

¹Bayer Pharma AG, Berlin, Germany,²Nuvisan ICB GmbH, Berlin, Germany,³Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Boston, MA

摘要 Abstract

KAT6A and KAT6B encode lysine acetyltransferases that catalyse the transfer of acetyl groups from acetyl-CoA to lysine residues on histone proteins, thereby influencing chromatin structure and gene expression. Amplification of these genes is observed in several cancers, with the 8p11-p12 chromosomal region-containing KAT6A-being increased in copy number in approximately 12-15% of breast cancer cases, leading to higher expression of chromatin-modifying enzymes. In this study, we introduce a novel series of acylsulfonamide-benzofuran compounds that function as selective inhibitors of KAT6A and KAT6B. These inhibitors were first identified via high-throughput screening and subsequently refined through computational modelling and co-crystallization studies. The lead compound from this series, BAY-184, demonstrated efficacy in an in vivo proof-of-concept experiment, confirming its potential as a tool for targeting KAT6A/B activity.

利益披露 Disclosure

A. ter Laak, Bayer Pharma AG Employment. R. Hillig, Nuvisan ICB GmbH Employment. S. Ferrara, Broad Institute of MIT and Harvard, Center for the Development of Therapeutics Employment. D. Korr, Nuvisan ICB GmbH Employment. P. Staller, Nuvisan ICB GmbH Employment. N. Barak, Bayer Pharma AG Employment. P. Lienau, Bayer Pharma AG Employment. S. Herbert, Bayer Pharma AG Employment. A. Fernandez, Bayer Pharma AG Employment. R. Neuhaus, Nuvisan ICB GmbH Employment. M. Gorjanacz, Bayer Pharma AG Employment. V. Puetter, Nuvisan ICB GmbH Employment. V. Badock, Nuvisan ICB GmbH Employment. W. Bone, Nuvisan ICB GmbH Employment. C. Strathdee, Broad Institute of MIT and Harvard, Center for the Development of Therapeutics Employment. F. Siegel, Bayer Pharma AG Employment. C. Schatz, Bayer Pharma AG Employment. N. Katrin, Nuvisan ICB GmbH Employment. O. Doehr, Bayer Pharma AG Employment. S. Gradl, Bayer Pharma AG Employment. I. Hartung, b Employment. M. Meyerson, Broad Institute of MIT and Harvard, Center for the Development of Therapeutics Employment. L. Bouche, Bayer Pharma AG Employment.

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