Proteome-wide dose-response measurements for the characterization of drug mechanism of action

Abstract

Almost all drugs exert their effects in a dose-dependent fashion, but a central challenge in drug discovery and pharmacology is to bridge the gap between observed phenotypic and the often complex underlying molecular mechanisms. Important questions to answer are: which proteins are physically bound by the compound, which pathways are engaged in the cell and how is the cell molecularly and physiologically reprogrammed en route to its eventual, drug-determined fate? In light of the advances in quantitative mass spectrometry speed and sensitivity over the past decade, it has become feasible to perform systematic full dose-response experiments at the level of: (1) target deconvolution; (2) pathway engagement; (3) proteome reprogramming; and (4) cellular consequences. Each enables the extraction of potency and effect size information for thousands of proteins and post-translational modification sites in parallel. In this mini-review, the conceptual framework of system-level dose-response measurements is outlined and key published studies are used to illustrate how such data inform successive layers of drug mechanisms of action.

Keywords

Chemical proteomics / Drug discovery / Mechanism of action / Dose-response omics

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the paper as follows: NB, FB, NK, AG and BK conceptualized the mini-review. NB, FB and NK analyzed the data. NB, FB, NK and AG visualized the data. BK wrote the manuscript with input from all authors. All authors contributed references, reviewed the results and approved the final version of the manuscript.

Data availability

All data generated or analyzed during this study are included in this published article.

Acknowledgments

The authors thank all members of the Kuster lab for fruitful discussions, assistance with creating data and data analysis that made this mini-review possible. This work was in part funded by the German Science Foundation (SFB/TRR 387, Grant No. 514894665; ProtACTion, Grant No. 525132892; SFB 1321, Grant No. 329628492), the German Cancer Aid (TACTIC, Grant No. 70115201), and the European Research Council (ERC Advanced Grant TOPAS, Grant No. 833710).

Conflict of interest

The authors declare that they have no conflict of interest. Bernhard Kuster is co-founder and shareholder of MSAID, and has no operational role in the company.

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