PO.ET09.02 · 实验与分子治疗

一类具有体内疗效的新型KAT6A/B抑制剂的研发

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 Authors & Affiliations

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

中文摘要

KAT6A和KAT6B编码赖氨酸乙酰转移酶,催化乙酰基从乙酰辅酶A转移至组蛋白的赖氨酸残基,从而影响染色质结构和基因表达。这些基因的扩增见于多种癌症,其中包含KAT6A的8p11-p12染色体区域在约12-15%的乳腺癌病例中拷贝数增加,导致染色质修饰酶的表达升高。在本研究中,我们介绍了一类新型的酰基磺酰胺-苯并呋喃化合物,作为KAT6A和KAT6B的选择性抑制剂。这些抑制剂首先通过高通量筛选鉴定,随后通过计算建模和共结晶研究进行优化。该系列的先导化合物BAY-184在体内概念验证实验中显示出疗效,证实了其作为靶向KAT6A/B活性工具的潜力。

查看英文原文 English 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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