"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"

作者全名："Li, Xin; Wu, Xiaowei; Nie, Shenyou; Zhao, Jidong; Yao, Yuan; Wu, Fangrui; Mishra, Chandra Bhushan; Ashraf-Uz-Zaman, Md; Moku, Bala Krishna; Song, Yongcheng"

作者地址："[Li, Xin; Wu, Xiaowei; Nie, Shenyou; Zhao, Jidong; Yao, Yuan; Wu, Fangrui; Mishra, Chandra Bhushan; Ashraf-Uz-Zaman, Md; Moku, Bala Krishna; Song, Yongcheng] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Pharmacol, 1 Baylor Plaza, Houston, TX 77030 USA; [Li, Xin; Song, Yongcheng] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA; [Wu, Xiaowei] Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China; [Wu, Xiaowei] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China; [Nie, Shenyou] Chongqing Med Univ, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400016, Peoples R China"

通信作者："Song, YC (通讯作者)，Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Pharmacol, 1 Baylor Plaza, Houston, TX 77030 USA.; Song, YC (通讯作者)，Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA."

来源：CANCERS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001103366300001

JCR分区：Q2

影响因子：5.2

年份：2023

卷号：15

期号：21

开始页：　

结束页：　

文献类型：Article

关键词：MLL-rearranged leukemia; super elongation complexes; small-molecule inhibitor; protein-protein interaction; cancer therapeutics

摘要："Simple Summary: Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for similar to 75% infant and 5-10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein-protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein-protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein-protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias. 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 IC50 values as low as 1.6 mu M. 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 EC50 values as low as 4.7 mu M. 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."

基金机构：United States National Institute of Health/National Cancer Institute [R01CA266057]; Cancer Prevention and Research Institute of Texas [RP220232]

基金资助正文：This work was supported by a grant (R01CA266057) from the United States National Institute of Health/National Cancer Institute and a grant (RP220232) from the Cancer Prevention and Research Institute of Texas to Y.S.