Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity
文献类型：期刊论文
| 作者 | Gong, Qineng2; Li, Chunpu1; Wang, Haojie2; Cao, Jinrui2; Li, Zuo2; Zhou, Mi2; Li, Yan2; Chu, Yong2; Liu, Hong1 ; Wang, Renxiao2
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| 刊名 | ACS OMEGA
 |
| 出版日期 | 2024-06-13 |
| 页码 | 28 |
| ISSN号 | 2470-1343 |
| DOI | 10.1021/acsomega.4c02021 |
| 通讯作者 | Chu, Yong(cy110@fudan.edu.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Wang, Renxiao(wangrx@fudan.edu.cn) |
| 英文摘要 | MCL-1, an antiapoptotic member of the BCL-2 family, is dysregulated and overexpressed in various tumors. In tumors with MCL-1 overexpression, selective inhibitors of MCL-1 are expected to overcome the drug resistance caused by BCL-2 inhibitors currently used in clinical treatment. Here, we employed docking-based virtual screening to identify an active hit, LC126, with binding affinity around 10 mu M for MCL-1 and BCL-2. Under the guidance of structure-based design, we obtained a few selective inhibitors of MCL-1 after three rounds of structural optimization. The representative compound GQN-B37-E exhibited binding affinity for MCL-1 at the submicromolar range (K-i = 0.6 mu M) without apparent binding to BCL-2 or BCL-X-L. N-15-heteronuclear single-quantum coherence NMR spectra suggested that this compound binds to the BH3-domain-binding pocket in the MCL-1 surface. Cellular assays revealed that GQN-B37-Me, the precursor of GQN-B37-E, is effective particularly on leukemia cells (such as H929 and MV-4-11) to induce caspase-dependent apoptosis. Its interaction with MCL-1 in cells was confirmed by coimmunoprecipitation. Administration of GQN-B37-Me to MV-4-11 xenograft mice at 50 mg/kg every 2 days for 20 days led to 43% tumor growth inhibition. GQN-B37-Me also exhibited reasonable in vitro stability in GSH and liver microsomes from several species. This new class of MCL-1 inhibitor may have potential to be further developed into a preclinical candidate for treating leukemia. |
| WOS关键词 | TARGETING MCL-1 ; CELL-DEATH ; CANCER ; FAMILY ; PROTEIN ; OPTIMIZATION ; MITOCHONDRIA ; SENSITIVITY ; HALLMARKS ; APOPTOSIS |
| 资助项目 | National Natural Science Foundation of China[81725022] ; National Natural Science Foundation of China[20S11900500] ; Science and Technology Commission of Shanghai Municipality |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001247369500001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311407]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chu, Yong; Liu, Hong; Wang, Renxiao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gong, Qineng,Li, Chunpu,Wang, Haojie,et al. Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity[J]. ACS OMEGA,2024:28. |
| APA | Gong, Qineng.,Li, Chunpu.,Wang, Haojie.,Cao, Jinrui.,Li, Zuo.,...&Wang, Renxiao.(2024).Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity.ACS OMEGA,28. |
| MLA | Gong, Qineng,et al."Discovery of Phenylpyrazole Derivatives as a New Class of Selective Inhibitors of MCL-1 with Antitumor Activity".ACS OMEGA (2024):28. |
入库方式： OAI收割
来源：上海药物研究所
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