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.

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 ₅₀为3.3μM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。