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Uncovering PROTAC Sensitivity and Efficacy by Multidimensional Proteome Profiling: A Case for STAT3

文献类型：期刊论文

作者Suo, Yuying1,9; Du, Daohai2; Chen, Chao3,4,8; Zhu, Hongwen1; Wang, Xiongjun5; Song, Nixue1; Lu, Dayun1; Yang, Yaxi3,4,7,9; Li, Jiacheng2; Wang, Jun2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-03-11
卷号67期号:6页码:4804-4818
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02371
通讯作者Zhou, Bing(zhoubing@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Zhou, Hu(zhouhu@simm.ac.cn)
英文摘要Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses. Through comparison between sensitive and insensitive cell lines, we revealed that STAT1 can be regarded as a biomarker for STAT3 PROTAC degrader, which was validated in cells, patient-derived organoids, and mouse models. These results set an example for a comprehensive description of the multidimensional PROTAC pharmacodynamic response and PROTAC drug sensitivity biomarker exploration.
WOS关键词SMALL-MOLECULE DEGRADER ; LINEAGE PLASTICITY ; DRUG-SENSITIVITY ; CANCER ; INTERFERON ; IL-6 ; ACTIVATION ; EXPRESSION ; PATHWAY ; CELLS
资助项目Natural Science Foundation of Shanghai Municipality[2022YFA1302900] ; National Key Research and Development Program[20XD1424900] ; Shanghai Young Excellent Academic Leader Program[81973166] ; Shanghai Young Excellent Academic Leader Program[81821005] ; Shanghai Young Excellent Academic Leader Program[92253303] ; Shanghai Municipal Science and Technology Major Project, National Natural Science Foundation of China[22XD1424600] ; Science and Technology Commission of Shanghai Municipality[22ZR1474100] ; Natural Science Foundation of Shanghai ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[ZYYCXTD-202004] ; National Administration of Traditional Chinese Medicine[2019B090904008] ; National Administration of Traditional Chinese Medicine[2021B0909050003] ; High-level new RD institute[SYS202205] ; Shandong Laboratory Program ; Department of Science and Technology of Guangdong Province ; National Centre for Protein Science Shanghai (Protein Expression and Purification system)[2023] ; Institutional Technology Service Center of Shanghai Institute of Materia Medica, CAS
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001184680100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310130]  
专题新药研究国家重点实验室
通讯作者Zhou, Bing; Luo, Cheng; Zhou, Hu
作者单位1.Chinese Acad Sci, Dept Analyt Chem, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Chem Biol,Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
5.Guangzhou Univ, Precise Genome Engn Ctr, Sch Life Sci, Guangzhou 510006, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
8.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
9.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Suo, Yuying,Du, Daohai,Chen, Chao,et al. Uncovering PROTAC Sensitivity and Efficacy by Multidimensional Proteome Profiling: A Case for STAT3[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(6):4804-4818.
APA Suo, Yuying.,Du, Daohai.,Chen, Chao.,Zhu, Hongwen.,Wang, Xiongjun.,...&Zhou, Hu.(2024).Uncovering PROTAC Sensitivity and Efficacy by Multidimensional Proteome Profiling: A Case for STAT3.JOURNAL OF MEDICINAL CHEMISTRY,67(6),4804-4818.
MLA Suo, Yuying,et al."Uncovering PROTAC Sensitivity and Efficacy by Multidimensional Proteome Profiling: A Case for STAT3".JOURNAL OF MEDICINAL CHEMISTRY 67.6(2024):4804-4818.

入库方式： OAI收割

来源：上海药物研究所

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