Abstract
Phenomenological screening of small molecule libraries for anticancer activity yields potentially interesting candidate molecules, with a bottleneck in the determination of drug targets and the mechanism of anticancer action. We have found that, for the protein target of a small-molecule drug, the abundance change in late apoptosis is exceptional compared to the expectations based on the abundances of co-regulated proteins. Based on this finding, a novel method to drug target deconvolution is proposed. In a proof of principle experiment, the method yielded known targets of several common anticancer agents among a few (often, just one) likely candidates identified in an unbiased way from cellular proteome comprising more than 4,000 proteins. A validation experiment with a different set of cells and drugs confirmed the findings. As an additional benefit, mapping most specifically regulated proteins on known protein networks highlighted the mechanism of drug action. The new method, if proven to be general, can significantly shorten drug target identification, and thus facilitate the emergence of novel anticancer treatments.
Highlights
Target-based discovery is the way pharmaceutical industry most often uses in searching for new drugs, with compound libraries screened for binding or activity against a known protein target
Functional Identification of Target by Expression Proteomics (FITExP) is based on our finding that, for the protein target of a small-molecule drug, the abundance change in late apoptosis is unexpectedly large compared to other proteins that are normally co-regulated with the drug target
In the proof-of-principle Experiment A, the objective was to test whether targets of common anticancer agents 5-FU, methotrexate (MTX), paclitaxel (PCTL), doxorubicin (DOXO) and tomudex (TDX) could be identified by expression proteomics
Summary
Target-based discovery is the way pharmaceutical industry most often uses in searching for new drugs, with compound libraries screened for binding or activity against a known protein target. Phenomenological screening of small molecule libraries is a “black-box”, target-agnostic approach, where compounds are interrogated in cell-based assays with a readout linked to a disease-relevant process (e.g., cancer cell apoptosis) This latter approach to drug discovery offers better chances for success. An alternative, general (or at least widely applicable) and more specific method that does not require chemical modification of the drug molecule, a priori knowledge of the drug action mechanism or signaling or metabolic pathways involved, would be highly valuable We describe such a method that we call Functional Identification of Target by Expression Proteomics (FITExP). It was suggested to treat the cells with other drugs, and filter away the proteins that will always be found strongly regulated in apoptosis
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