Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening
文献类型：期刊论文
| 作者 | Duan, Zhe1; Liu, Jingqiu2; Niu, Liping3; Wang, Jun2; Feng, Mingqian1; Chen, Hua3; Luo, Cheng2
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-08-01 |
| 卷号 | 27期号:15页码:3229-3236 |
| 关键词 | IDH1 mutation High-throughput screening Pan-inhibitor 2-HG Gliomas |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2019.05.040 |
| 通讯作者 | Feng, Mingqian(fengmingqian@mail.hzau.edu.cn) ; Chen, Hua(hua-todd@hbu.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn) |
| 英文摘要 | IDH1 mutations are early events in the development of IDH-mutant gliomas and leukemias and are associated with various regulation of molecular process. Mutations of active site in IDH1 could lead to high levels of 2-HG and the suppression of cellular differentiation, while these changes can be reversed by molecule inhibitors target mutant IDH1. Here, through in-house developed enzymatic assay-based high throughput screening platform, we discovered DC_H31 as a novel IDH1-R132H/C inhibitor, with the IC50 value of 0.41 mu mol/L and 2.7 mu mol/L respectively. In addition, saturable SPR binding assay indicated that DC_H31 bound to IDH1-R132H/C due to specific interaction. Further computational docking studies and structure-activity relationship (SAR) suggest that DC_H31 could occupy the allosteric pocket between the two monomers of IDH1-R132H homodimer, which accounts for its inhibitory ability. And it is possible to conclude that DC_H31 acts via an allosteric mechanism of inhibition. At the cellular level, DC_H31 could inhibit cell proliferation, promote cell differentiation and reduce the production of 2-HG with a dose-dependent manner in HT1080 cells. Taken together, DC_H31 is a potent selective inhibitor of IDH1-R132H/C both in vitro and in vivo, which can promote the development of more potent pan-inhibitors against IDH1-R132H/C through further structural decoration and provide a new insight for the pharmacological treatment of gliomas. |
| WOS关键词 | ISOCITRATE DEHYDROGENASE 1 ; ACUTE MYELOID-LEUKEMIA ; ONCOMETABOLITE 2-HYDROXYGLUTARATE ; 2 MUTATIONS |
| 资助项目 | Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (NFPS), Zhanjiang Lab ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; K.C. Wong Education Foundation ; China Postdoctoral Science Foundation[2017M621571] ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000476649400003 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289185]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Feng, Mingqian; Chen, Hua; Luo, Cheng |
| 作者单位 | 1.Huazhong Agr Univ, Coll Life Sci & Technol, Wuhan 430070, Hubei, Peoples R China 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Hebei Univ, Key Lab Chem Biol Hebei Prov, Coll Chem & Environm Sci, Baoding 071002, Peoples R China |
| 推荐引用方式 GB/T 7714 | Duan, Zhe,Liu, Jingqiu,Niu, Liping,et al. Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(15):3229-3236. |
| APA | Duan, Zhe.,Liu, Jingqiu.,Niu, Liping.,Wang, Jun.,Feng, Mingqian.,...&Luo, Cheng.(2019).Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening.BIOORGANIC & MEDICINAL CHEMISTRY,27(15),3229-3236. |
| MLA | Duan, Zhe,et al."Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening".BIOORGANIC & MEDICINAL CHEMISTRY 27.15(2019):3229-3236. |
入库方式： OAI收割
来源：上海药物研究所
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