Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader
文献类型：期刊论文
| 作者 | Zhu, Cheng-Liang4,7,9; Luo, Xiaomin10; Tian, Tian8; Rao, Zijian9; Wang, Hanlin1; Zhou, Zhesheng9; Mi, Tian6; Chen, Danni9; Xu, Yongjin2; Wu, Yizhe |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-08-05 |
| 卷号 | 238页码:15 |
| ISSN号 | 0223-5234 |
| 关键词 | AKT Protein kinase B PROTAC Chemical degrader Rational design |
| DOI | 10.1016/j.ejmech.2022.114459 |
| 通讯作者 | Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn) |
| 英文摘要 | AKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a structurally unique AKT targeting warhead derived from the pyrazole-furan conjugated piperidine derivatives. It induces selective degradation of all three isoforms of AKT and exhibits efficacious anti-proliferation against several human hematological cancers. Notably, B4 demonstrates potent inhibition of AKT downstream signaling superior to its parental inhibitor. Together with its active analogs, B4 expands the arsenal of AKT chemical degraders as a valuable probe to uncover AKTs new functions and as a potential drug candidate to treat cancer. |
| WOS关键词 | MANTLE CELL LYMPHOMA ; BIOLOGICAL EVALUATION ; PATHWAY ; DEGRADATION ; INHIBITION ; DERIVATIVES ; BTK ; IBRUTINIB ; MK-2206 ; TARGET |
| 资助项目 | National Natural Science Foundation of China[82173660] ; National Natural Science Foundation of China[82103975] ; Natural Science Foundation of Zhejiang Province[LR21H300003] |
| 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:000806746400005 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/301551]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhou, Yubo; Li, Jia; Dong, Xiaowu |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Shanghai 200032, Peoples R China 2.Canc Hosp Univ Chinese Acad Sci, Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc, Hangzhou 310005, Peoples R China 3.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China 4.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310016, Peoples R China 5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan Tsuihang New Di 528400, Guangdon, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Ctr Drug Safety Evaluat & Res ZJU, Hangzhou 310058, Peoples R China 8.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China 9.Zhejiang Univ, Inst Pharmacol & Toxicol, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China 10.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Cheng-Liang,Luo, Xiaomin,Tian, Tian,et al. Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,238:15. |
| APA | Zhu, Cheng-Liang.,Luo, Xiaomin.,Tian, Tian.,Rao, Zijian.,Wang, Hanlin.,...&Dong, Xiaowu.(2022).Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,238,15. |
| MLA | Zhu, Cheng-Liang,et al."Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 238(2022):15. |
入库方式： OAI收割
来源：上海药物研究所
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