Importance of Quantifying Drug-Target Engagement in Cells

Jakub Stefaniak; Kilian V M Huber

doi:10.1021/acsmedchemlett.9b00570

Importance of Quantifying Drug-Target Engagement in Cells

ACS Med Chem Lett. 2020 Mar 6;11(4):403-406. doi: 10.1021/acsmedchemlett.9b00570. eCollection 2020 Apr 9.

Authors

Jakub Stefaniak^{1

2

3}, Kilian V M Huber^{1

2}

Affiliations

¹ Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, U.K.
² Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
³ Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, U.K.

Abstract

Measuring and quantifying the binding of a drug to a protein target inside living cells and thereby correlating biochemical or biophysical activity with target engagement in cells or tissue represents a key step in target validation and drug development. A prototypic target engagement assay should allow for unbiased determination of small molecule-protein interactions in order to confirm cellular mechanism-of-action (MoA) while avoiding major artificial perturbations of cellular homeostasis and integrity. Recently, several new additions to the chemical biology toolbox have expanded our ability to study drug action in intact cells and enabled surveying of intracellular residence time and binding kinetics, which are particularly important for potent receptor ligands and therapeutic moieties with limited therapeutic index.