高亲和力CHD1染色质结构域抑制剂的开发
Development of High-Affinity CHD1 Chromodomain Inhibitors.
摘要(中文译文)
染色质重塑因子CHD1是前列腺癌（PCa）中基因活性的调控因子及潜在药物靶点，其含有串联染色质结构域（tCD），可结合组蛋白H3第4位赖氨酸三甲基化修饰（H3K4me3）。我们开发了首个亚微摩尔级抑制剂（ 和 ），靶向CHD1 tCD的H3K4me3结合位点，其 值分别为0.15 μM和0.14 μM。这些基于喹啉类化合物的共晶结构揭示了芳香笼相互作用以及H3K4me3肽结合口袋其他部分的延伸配体接触是高亲和力配体结合的主要决定因素。 和 能够与细胞裂解液中的内源性CHD1或细胞中的外源性CHD1 tCD结合。此外，我们提供了针对一组甲基赖氨酸阅读器及表观遗传酶的选择性证据，以及对PCa细胞活力的损害作用。由于其高效力和明确的结合模式，我们的配体为进一步优化提供了新方向。
Abstract
The chromatin remodeler CHD1, a regulator of gene activity and potential drug target in prostate cancer (PCa), contains a tandem chromodomain (tCD) binding histone H3 trimethylated at lysine 4 (H3K4me3). We developed the first submicromolar inhibitors ( and ) that target the H3K4me3 binding site of the CHD1 tCD with values of 0.15 μM and 0.14 μM, respectively. Co-crystal structures of these quinoline-based compounds revealed aromatic cage interactions and extended ligand contacts in other parts of the H3K4me3 peptide pocket as the main determinants of high-affinity ligand binding. and engage endogenous CHD1 in cell lysates or the exogenous CHD1 tCD in cells. Furthermore, we provide evidence for selectivity against a panel of methyl-lysine readers and epigenetic enzymes as well as impairment of PCa cell viability. Due to their high potency and defined binding mode, our ligands offer new directions for further optimization.
如何引用
AMA
Holger Greschik, Florian Friedrich, Ludwig Seifert, Farnoush Mousavizadeh, Francesco Fiorentino, Johannes Walz, et al. Development of High-Affinity CHD1 Chromodomain Inhibitors.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.5c03690.
APA
Holger Greschik, Florian Friedrich, Ludwig Seifert, Farnoush Mousavizadeh, Francesco Fiorentino, Johannes Walz, et al (2026). Development of High-Affinity CHD1 Chromodomain Inhibitors.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.5c03690
GB/T 7714
Holger Greschik, Florian Friedrich, Ludwig Seifert, Farnoush Mousavizadeh, Francesco Fiorentino, Johannes Walz, et al. Development of High-Affinity CHD1 Chromodomain Inhibitors.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.5c03690.
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