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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

文献类型：期刊论文

作者Li, Xin4,5; Wu, Xiaowei2,3,5; Nie, Shenyou1,5; Zhao, Jidong5; Yao, Yuan5; Wu, Fangrui5; Mishra, Chandra Bhushan5; Ashraf-Uz-Zaman, Md5; Moku, Bala Krishna5; Song, Yongcheng4,5
刊名CANCERS
出版日期2023-11-01
卷号15期号:21页码:28
关键词MLL-rearranged leukemia super elongation complexes small-molecule inhibitor protein-protein interaction cancer therapeutics
DOI10.3390/cancers15215283
通讯作者Song, Yongcheng(ysong@bcm.edu)
英文摘要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.
WOS关键词ACUTE LYMPHOBLASTIC-LEUKEMIA ; ACUTE MYELOID-LEUKEMIA ; GENE-EXPRESSION ; MLL GENE ; REARRANGEMENTS ; PARTNERS ; CANCER ; MYC ; TRANSLOCATIONS ; METHYLATION
资助项目United States National Institute of Health/National Cancer Institute[R01CA266057] ; Cancer Prevention and Research Institute of Texas[RP220232]
WOS研究方向Oncology
语种英语
WOS记录号WOS:001103366300001
出版者MDPI
源URL[http://119.78.100.183/handle/2S10ELR8/307845]  
专题中国科学院上海药物研究所
通讯作者Song, Yongcheng
作者单位1.Chongqing Med Univ, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400016, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA
5.Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Pharmacol, 1 Baylor Plaza, Houston, TX 77030 USA
推荐引用方式
GB/T 7714		 Li, Xin,Wu, Xiaowei,Nie, Shenyou,et al. 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[J]. CANCERS,2023,15(21):28.
APA Li, Xin.,Wu, Xiaowei.,Nie, Shenyou.,Zhao, Jidong.,Yao, Yuan.,...&Song, Yongcheng.(2023).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.CANCERS,15(21),28.
MLA Li, Xin,et al."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".CANCERS 15.21(2023):28.

入库方式： OAI收割

来源：上海药物研究所

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