Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC Chemical Biology Pub Date : 2023-12-18 DOI:10.1039/D3CB00214D
Gloria Ortiz, James E. Longbotham, Sophia L. Qin, Meng Yao Zhang, Gregory M. Lee, R. Jeffrey Neitz, Mark J. S. Kelly, Michelle R. Arkin and Danica Galonić Fujimori
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Abstract

PHD fingers are a type of chromatin reader that primarily recognize chromatin as a function of lysine methylation state. Dysregulated PHD fingers are implicated in various human diseases, including acute myeloid leukemia. Targeting PHD fingers with small molecules is considered challenging as their histone tail binding pockets are often shallow and surface-exposed. The KDM5A PHD1 finger regulates the catalytic activity of KDM5A, an epigenetic enzyme often misregulated in cancers. To identify ligands that disrupt the PHD1-histone peptide interaction, we conducted a high-throughput screen and validated hits by orthogonal methods. We further elucidated structure–activity relationships in two classes of compounds to identify features important for binding. Our investigation offers a starting point for further optimization of small molecule PHD1 ligands.

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通过高通量筛选确定 KDM5A PHD1 手指的配体
PHD 指是一种染色质阅读器,主要识别染色质赖氨酸甲基化状态。PHD指的失调与包括急性髓性白血病在内的多种人类疾病有关。用小分子靶向 PHD 手指具有挑战性,因为它们的组蛋白尾部结合口袋通常较浅且表面暴露。PHD1 指调节 KDM5A 的催化活性,而 KDM5A 是一种在癌症中经常被误调的表观遗传酶。为了鉴定能破坏 PHD1-组蛋白肽相互作用的配体,我们进行了高通量筛选,并通过正交方法验证了命中配体。我们进一步阐明了两类化合物的结构-活性关系,以确定结合的重要特征。我们的研究为进一步优化小分子 PHD1 配体提供了一个起点。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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