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Matrix-Augmented Pooling Strategy for High-Throughput Target Deconvolution Reveals Cell Type Off-targets and Responses

ABSTRACT: Target deconvolution is a crucial but costly and time-consuming task that hinder 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 perform target deconvolution of the 15 drugs across 5 cell lines. Our profiling revealed drug-target interactions can differ vastly in targets and binding affinity across cell lines. We further validated BRAF and CSNK2A are the potential off-targets of bafetinib and abemaciclib, respectively. This work presents the largest target profiling of structurally diverse drugs across multiple cell lines to date.

ORGANISM(S): Homo Sapiens

SUBMITTER: Chris Tan

PROVIDER: PXD043882 | iProX | Wed Jul 19 00:00:00 BST 2023

REPOSITORIES: iProX

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