Perturbation-Based Proteomic Correlation Profiling as a Target Deconvolution Methodology

Abstract

Molecular target identification of small molecules, so-called target deconvolution, is a major obstacle to phenotype-based drug discovery. Here, we developed an approach called perturbation-based proteomic correlation profiling (PPCP) utilizing the correlation between protein quantity and binding activity of compounds under cellular perturbation by gene silencing and successfully identified lanosterol synthase as a molecular target of TGF-β pathway inhibitor. This PPCP concept was extended to the use of a cell line panel and provides a new option for target deconvolution.

Keywords: TGF-β pathway inhibitor; cell line panel; chemical proteomics; gene knockdown; lanosterol synthase; mass spectrometry; perturbation-based proteomic correlation profiling; phenotype-based drug discovery; radioactive compound binding assay; target deconvolution.