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Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma

文献类型：期刊论文

作者Zhang, Jingyu1; Che, Jinxin1; Luo, Xiaomin2,3; Wu, Mingfei1; Kan, Weijuan3; Jin, Yuheng1; Wang, Hanlin3,4; Pang, Ao1; Li, Cong3; Huang, Wenhai5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-06-07
卷号65期号:13页码:9096–9125
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00324
文献子类Article
英文摘要Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTKPROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.
WOS关键词PRINCIPAL COMPONENT ANALYSIS
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000822857600001
源URL[http://119.78.100.183/handle/2S10ELR8/309341]  
专题新药研究国家重点实验室
通讯作者Che, Jinxin; Zhou, Yubo; Li, Jia; Dong, Xiaowu
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China;
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China;
3.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
4.Fudan Univ, Sch Pharm, Shanghai 200032, Peoples R China;
5.Hangzhou Med Coll, Key Lab Neuropsychiat Drug Res Zhejiang Prov, Hangzhou 310058, Peoples R China;
6.Chinese Acad Sci, Dept Lymphoma, Inst Basic Med & Canc, Canc Hosp,Univ Chinese Acad Sci,Zhejiang Canc Hos, Hangzhou 310005, Peoples R China;
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China;
8.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China;
9.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Jingyu,Che, Jinxin,Luo, Xiaomin,et al. Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(13):9096–9125.
APA Zhang, Jingyu.,Che, Jinxin.,Luo, Xiaomin.,Wu, Mingfei.,Kan, Weijuan.,...&Dong, Xiaowu.(2022).Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,65(13),9096–9125.
MLA Zhang, Jingyu,et al."Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 65.13(2022):9096–9125.

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来源：上海药物研究所

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