Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC
文献类型：期刊论文
| 作者 | Guo, Siqi2; Jia, Tongguan1; Xu, Xiaoming1; Yang, Feng3; Xiao, Senhao3; Hou, Zeng3,4,5; Xu, Hesong3,4,5; Ma, Shuyuan3,4,5; Liu, Xiao3,4; Luo, Cheng3,4,5
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-02-15 |
| 卷号 | 248页码:14 |
| ISSN号 | 0223-5234 |
| 关键词 | ENL Inhibitor YEATS domain Histone lysine acetylation Benzimidazole derivatives Acute myeloid leukemia |
| DOI | 10.1016/j.ejmech.2023.115093 |
| 通讯作者 | Jiang, Hualiang(hljiang@simm.ac.cn) ; Chen, Hua(hua-todd@163.com) ; Chen, Shijie(shijiechen@simm.ac.cn) |
| 英文摘要 | Eleven-Nineteen-Leukemia Protein (ENL) containing YEATS domain, a potential drug target, has emerged as a reader of lysine acetylation. SGC-iMLLT bearing with benzimidazole scaffold was identified as an effective ENL inhibitor, but with weak activity against mixed-lineage leukemia (MLL)-rearranged cells proliferation. In this study, a series of compounds were designed and synthesized by structural optimization on SGC-iMLLT. All the compounds have been evaluated for their ENL inhibitory activities. The results showed that compounds 13, 23 and 28 are the most potential ones with the IC50 values of 14.5 +/- 3.0 nM, 10.7 +/- 5.3 nM, and 15.4 +/- 2.2 nM, respectively, similar with that of SGC-iMLLT. They could interact with ENL protein and strengthen its thermal stability in vitro. Among them, compound 28 with methyl phenanthridinone moiety replacement of indazole in SGC-iMLLT, exhibited significantly inhibitory activities towards MV4-11 and MOLM-13 cell lines with IC50 values of 4.8 mu M and 8.3 mu M, respectively, exhibiting-7 folds and-9 folds more potent inhibition of cell growth than SGC-iMLLT. It could also increase the ENL thermal stability while SGC-iMLLT had no obvious effect on leukemia cells. Moreover, compound 28 could downregulate the expression of target gene MYC either alone or in combination with JQ-1 in cells, which was more effective than SGC-iMLLT. Besides, in vivo pharmacokinetic studies showed that the PK properties for compound 28 was much improved over that of SGC-iMLLT. These observations suggested compound 28 was a potential ligand for ENL-related MLL chemotherapy. |
| WOS关键词 | LINKS HISTONE ACETYLATION ; AF9 YEATS DOMAIN ; TRANSCRIPTION ; RECOGNITION ; CROTONYLATION ; MUTATIONS ; READER ; TAF14 |
| 资助项目 | National Key R&D Program of China[2022YFC3400500] ; Science and Technology Commission of Shanghai Municipality[21ZR1474700] ; Youth Innovation Promotion Association of CAS[2022279] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[21772031] ; Natural Science Interdisciplinary Research Program of Hebei University[DXK201903] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000922169000001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/303681]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang; Chen, Hua; Chen, Shijie |
| 作者单位 | 1.Hebei Univ, Coll Chem & Mat Sci, Key Lab Chem Biol Hebei Prov, Baoding 071002, Peoples R China 2.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Siqi,Jia, Tongguan,Xu, Xiaoming,et al. Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,248:14. |
| APA | Guo, Siqi.,Jia, Tongguan.,Xu, Xiaoming.,Yang, Feng.,Xiao, Senhao.,...&Chen, Shijie.(2023).Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,248,14. |
| MLA | Guo, Siqi,et al."Design, synthesis of novel benzimidazole derivatives as ENL inhibitors suppressing leukemia cells viability via downregulating the expression of MYC".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 248(2023):14. |
入库方式： OAI收割
来源：上海药物研究所
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