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Target deconvolution with matrix-augmented pooling strategy reveals cell-specific drug-protein interactions

文献类型： 外文期刊

作者： Ji, Hongchao 1 ; Lu, Xue 1 ; Zhao, Shiji 3 ; Wang, Qiqi 1 ; Liao, Bin 1 ; Bauer, Ludwig G. 4 ; Huber, Kilian V. M. 4 ; Luo, Ray 3 ; Tian, Ruijun 1 ; Tan, Chris Soon Heng 1 ;

作者机构： 1.Southern Univ Sci & Technol, Dept Chem & Res Ctr Chem Biol & Om Anal, Coll Sci, Shenzhen 518055, Guangdong, Peoples R China

2.Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Guangdong Lab Lingnan Modern Agr, Shenzhen Branch,Genome Anal Lab Minist Agr & Rural, Shenzhen 518120, Peoples R China

3.Univ Calif Irvine, Dept Mol Biol & Biochem, Dept Chem & Biomol Engn, Dept Mat Sci & Engn,Dept Biomed Engn, Irvine, CA 92697 USA

4.Nuffield Dept Med, Ctr Med Discovery, Oxford OX3 7FZ, England

5.Nuffield Dept Med, Target Discovery Inst, Oxford OX3 7FZ, England

期刊名称：CELL CHEMICAL BIOLOGY （ 影响因子：8.6； 五年影响因子：8.8 ）

ISSN： 2451-9456

年卷期： 2023 年 30 卷 11 期

页码：

收录情况： SCI

摘要： Target deconvolution is a crucial but costly and time-consuming task that hinders large-scale profiling for drug discovery. We present a matrix-augmented pooling strategy (MAPS) which mixes multiple drugs into samples with optimized permutation and delineates targets of each drug simultaneously with mathematical processing. We validated this strategy with thermal proteome profiling (TPP) testing of 15 drugs concurrently, increasing experimental throughput by 60x while maintaining high sensitivity and specificity. Benefiting from the lower cost and higher throughput of MAPS, we performed target deconvolution of the 15 drugs across 5 cell lines. Our profiling revealed that drug-target interactions can differ vastly in targets and binding affinity across cell lines. We further validated BRAF and CSNK2A2 as potential off-targets of bafetinib and abemaciclib, respectively. This work represents the largest thermal profiling of structurally diverse drugs across multiple cell lines to date.

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