文章：

AF9/ENL与AF4或DOT1L间蛋白质-蛋白质相互作用的小分子抑制剂的发现、构效关系及体外抗癌活性研究

Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L

原文发布日期：3 November 2023

DOI: 10.3390/cancers15215283

类型: Article

开放获取: 是

英文摘要：

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC50values as low as 1.6 μM. Structure–activity relationship studies of 77 benzothiophene and related indole and benzofuran compounds show that a 4-piperidin-1-ylphenyl or 4-pyrrolidin-1-ylphenyl substituent is essential for the activity. The inhibitors suppressed expression of MLL target genes HoxA9, Meis1 and Myc, and selectively inhibited proliferation of MLL-r and other acute myeloid leukemia cells with EC50values as low as 4.7 μM. These inhibitors are useful chemical probes for biological studies of AF9/ENL, as well as pharmacological leads for further drug development against MLL-r and other leukemias.

摘要翻译： 

涉及混合谱系白血病（MLL）基因的染色体易位导致5-10%的急性白血病，其临床预后较差。最常见的MLL融合伴侣蛋白AF9/ENL与AF4或组蛋白甲基转移酶DOT1L之间的蛋白质-蛋白质相互作用（PPI）是MLL重排（MLL-r）白血病的药物靶点。研究发现数种苯并噻吩-甲酰胺类化合物可作为这些PPI的新型抑制剂，其IC50值低至1.6 μM。通过对77种苯并噻吩及相关吲哚和苯并呋喃类化合物的构效关系研究，证实4-哌啶-1-基苯基或4-吡咯烷-1-基苯基取代基是维持活性的关键结构。这些抑制剂能有效抑制MLL靶基因HoxA9、Meis1和Myc的表达，并选择性抑制MLL-r及其他急性髓系白血病细胞的增殖，其EC50值最低可达4.7 μM。该类抑制剂不仅可作为研究AF9/ENL生物学功能的化学探针，更为针对MLL-r及其他白血病的后续药物研发提供了先导化合物。

原文链接：

Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L