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.

中文翻译：

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通过高通量筛选鉴定 KDM5A PHD1 指的配体

PHD Finger 是一种染色质读取器，主要将染色质识别为赖氨酸甲基化状态的函数。PHD 手指失调与多种人类疾病有关，包括急性髓性白血病。用小分子靶向 PHD 手指被认为具有挑战性，因为它们的组蛋白尾部结合袋通常很浅且表面暴露。KDM5A PHD1 指调节 KDM5A 的催化活性，KDM5A 是一种在癌症中经常被错误调节的表观遗传酶。为了鉴定破坏 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。我们进一步阐明了两类化合物的结构-活性关系，以确定对结合重要的特征。我们的研究为进一步优化小分子 PHD1 配体提供了起点。