Abstract

Overexpression of E26 transformation-specific (ETS) PEA3 subfamily transcription factor (TF) ETV1 is reportedly oncogenic and metastatic in several cancers. Albeit, a few synthetic small molecule inhibitors of ETV1 have been identified to date. In this context, we hereby proposed a phytochemical lead development scheme to gather inhibitor scaffolds for ETV1. A fingerprint-based similarity search was conducted to screen plant compounds structurally similar to known ETV1 perturbagens. At default cutoffs, 20 compounds were retrieved whose pharmacokinetic, docking, and scaffold analysis rendered eight compounds for final evaluation in HeLa cells by MTT assay. CID7732 (p-anisidine) belonging to the subclass aminophenyl ethers was emerged as a promising anticancer agent with an IC50 of 27.769 µg/mL. This is the first natural product-based chemical hunt carried out for ETV1 repressors.

Communicated by Ramaswamy H. Sarma

摘要

据报道，E26 转化特异性 (ETS) PEA3 亚家族转录因子 (TF) ETV1 的过度表达在几种癌症中具有致癌性和转移性。尽管如此，迄今为止已经确定了一些合成的 ETV1 小分子抑制剂。在这种情况下，我们在此提出了一种植物化学先导开发计划，以收集 ETV1 的抑制剂支架。进行了基于指纹的相似性搜索，以筛选结构与已知 ETV1 扰动剂相似的植物化合物。在默认临界值下，检索到 20 种化合物，其药代动力学、对接和支架分析使 8 种化合物通过 MTT 测定在 HeLa 细胞中进行最终评估。CID7732 ( p-茴香胺）属于亚类氨基苯醚，作为一种有前途的抗癌剂出现，IC50 为 27.769 µg/mL。这是针对 ETV1 阻遏物进行的第一次基于天然产物的化学搜索。

由 Ramaswamy H. Sarma 交流