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Ligand-based optimization and biological evaluation of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide derivatives as potent intrinsically disordered protein c-Myc inhibitors
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-11-24 , DOI: 10.1016/j.bmcl.2020.127711
Limin Chen 1 , Beiming Cheng 1 , Qi Sun 2 , Luhua Lai 3
Affiliation  

The transcription factor c-Myc is a well-known onco-protein and an intrinsically disordered protein (IDP). As its aberrant expression is frequently observed in various human cancers, c-Myc is considered as a key drug target. However, due to its high conformational flexibility, directly targeting c-Myc remains difficult. Here we explored the structure–activity relationships (SAR) of N-(2,2,2-trichloro-1-(3-phenylthioureido)ethyl)acetamide compounds and reported sixteen novel active compounds. Among them, compound PKUMDL-CLM-32 (hereafter, 32) showed the best anti-proliferation activity in cells with an EC50 of 3.3 μM. We demonstrated that 32 directly disrupts c-Myc/Max interaction and induces the degradation of c-Myc protein in cells. We showed that 32 induces cell cycle arrest at S phase and promotes apoptosis of HL-60 cells. This study provides an example of using ligand-based analysis to optimize IDP ligands.



中文翻译:

基于配体的N-(2,2,2-三氯-1-(3-苯基硫脲基)乙基)乙酰胺衍生物作为潜在的内在无序蛋白c-Myc抑制剂的优化和生物学评估

转录因子c-Myc是众所周知的癌蛋白和内在无序蛋白(IDP)。由于在各种人类癌症中经常观察到其异常表达,因此c-Myc被认为是关键的药物靶标。但是,由于其高度的构象灵活性,直接靶向c-Myc仍然很困难。在这里,我们探讨了N-(2,2,2-三氯-1-(3-苯基硫脲基)乙基)乙酰胺化合物的结构-活性关系(SAR),并报道了16种新型活性化合物。其中,化合物PKUMDL-CLM-32(以下称32)在EC 503.3μM的细胞中表现出最佳的抗增殖活性。我们证明了32直接破坏c-Myc / Max相互作用并诱导细胞中c-Myc蛋白降解。我们发现32诱导细胞周期停滞在S期并促进HL-60细胞凋亡。这项研究提供了一个使用基于配体的分析优化IDP配体的例子。

更新日期:2020-12-01
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