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

Ji, Hongchao1,2; Lu, Xue1; Zhao, Shiji3; Wang, Qiqi1; Liao, Bin1; Bauer, Ludwig G.4,5; Huber, Kilian V. M.4,5; Luo, Ray3; Tian, Ruijun1; Tan, Chris Soon Heng1

2023-11-16

10.1016/j.chembiol.2023.08.002

CELL CHEMICAL BIOLOGY   影响因子和分区

2451-9456

2451-9448

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.

SCI

英语

第一 ; 通讯

Shenzhen Innovation of Science and Technology Commission Grant[JCY20200109140814408] ; National Natural Science Foundation of China["22074060","22103036","22150610470"] ; National Institutes of Health[GM130367] ; Innovative Medicines Initiative 2 Joint Undertaking (JU)[875510]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:001114136600001

CELL PRESS

Web of Science

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

Ji, Hongchao,Lu, Xue,Zhao, Shiji,et al. Target deconvolution with matrix-augmented pooling strategy reveals cell-specific drug-protein interactions[J]. CELL CHEMICAL BIOLOGY,2023,30(11).

Ji, Hongchao.,Lu, Xue.,Zhao, Shiji.,Wang, Qiqi.,Liao, Bin.,...&Tan, Chris Soon Heng.(2023).Target deconvolution with matrix-augmented pooling strategy reveals cell-specific drug-protein interactions.CELL CHEMICAL BIOLOGY,30(11).

Ji, Hongchao,et al."Target deconvolution with matrix-augmented pooling strategy reveals cell-specific drug-protein interactions".CELL CHEMICAL BIOLOGY 30.11(2023).