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Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML

文献类型：期刊论文

作者Lian, Xuanmin5; Gao, Yue3,4; Du, Wenjing5; Xu, Chengcheng4; Dong, Xiaowu5; Che, Jinxin5; Zhou, Yubo3,4; Li, Jia3,4; Liu, Tao1,2,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-10-23
卷号68期号:20页码:21939-21961
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c02332
通讯作者Che, Jinxin(chejx@zju.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Tao(lt601@zju.edu.cn)
英文摘要FLT3 inhibitors (FLT3i) are effective for treating acute myeloid leukemia (AML), but acquired and adaptive resistance pose significant challenges. Therefore, finding a novel AML therapy that overcomes resistance is necessary. Proteolysis-targeting chimeras (PROTACs) are a new approach in drug discovery, offering a promising strategy for targeting FLT3 mutations in the development of effective anti-AML therapies. Our previous study found that simultaneously targeting FLT3 and CHK1 can upregulate p53 level and downregulate c-Myc level, thus overcoming adaptive resistance. We combined the merits of both PROTACs and dual targeting drugs to design a series of dual FLT3/CHK1 PROTACs. The optimal compound A28 effectively degraded FLT3 and CHK1 in a proteasome-dependent manner. Also, A28 potently inhibited FLT3 signaling, downregulated c-Myc, and upregulated p53 level. Further studies indicated that A28 had the potential to overcome acquired and adaptive resistance. Importantly, weekly intravenous administration of A28 sustained tumor growth suppression in MV-4-11 subcutaneous xenograft models.
WOS关键词ACUTE MYELOID-LEUKEMIA ; RESISTANCE ; MUTATIONS ; QUIZARTINIB ; INHIBITORS ; BIOLOGY ; TARGET ; ROLES
资助项目Key Research and Development Program of Zhejiang Province[2024C03058] ; Zhejiang Provincial Key Research & Development Plan[2023000003] ; Zhejiang Provincial Key Research & Development Plan[2019B090904008] ; Guangdong High-level new RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001587024500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321642]  
专题中国科学院上海药物研究所
通讯作者Che, Jinxin; Zhou, Yubo; Li, Jia; Liu, Tao
作者单位1.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China
2.Zhejiang Univ, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Zijingang Campus, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Lian, Xuanmin,Gao, Yue,Du, Wenjing,et al. Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(20):21939-21961.
APA Lian, Xuanmin.,Gao, Yue.,Du, Wenjing.,Xu, Chengcheng.,Dong, Xiaowu.,...&Liu, Tao.(2025).Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML.JOURNAL OF MEDICINAL CHEMISTRY,68(20),21939-21961.
MLA Lian, Xuanmin,et al."Development of Dual FLT3 and CHK1 PROTACs for the Treatment of AML".JOURNAL OF MEDICINAL CHEMISTRY 68.20(2025):21939-21961.

入库方式： OAI收割

来源：上海药物研究所

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