Having demonstrated the compatibility of ECAL with a wide range of ligand-protein pairs, ECAL was field-tested within the context of chemoproteomic profiling of known ligands in live cell culture. Considering that this is the first instance of ECAL in live cell systems, the biocompatibility of the electrochemical system on cell viability was evaluated with the finding that short reaction times employed within our labeling experiments do not impact cell viability (Figure ). Using dasatinib or JQ1 equipped with DZE and desthiobiotin (compounds 17 or 19) we set out to identify endogenous proteins labeled within HCT116 colorectal cancer cells (Figure ). Cells were incubated with the DZE probes followed by electrochemical activation to initiate covalent protein labeling followed by enrichment for subsequent proteomic analysis (Figure ). Targeted labeling using JQ1-DZE-desthiobiotin probe 19 in HCT116 cells resulted in the significant enrichment of the known binding partners BRD4 and BRD2 (Figure ). In contrast, when Dasatinib-DZEdesthiobiotin 17 was used for targeted protein labeling, SRC kinase (a known dasatinib ligand) was identified as a highly enriched target (Figure ). Comparing the 25 most enriched proteins detected from JQ1-DZE-desthiobiotin 19 and Dasatinib-DZE-desthiobiotin 17 targeted labeling led to no observed direct protein overlap (Figure ) as well as distinct differences in enriched GO-terms for biological and molecular functions (Figure and). The generality of our ECAL technology was further showcased through CA-DZE 15 targeted labeling of CA in HT29 cells that resulted in increased CA enrichment in both hypoxic and normoxic conditions (Figure ). These results highlight the ability of the ECAL technology to achieve selective chemoproteomic detection of ligand targets in complex biological systems (Figure ). Regarding how the labeling of endogenous proteins was achieved using an exterior electrode, at this moment we consider that both direct and mediated oxidation pathways are possible. It is known that direct exchange of electrons is possible through cell membranes such as the case in red blood cells. On the other hand, mediated oxidation is also feasible considering the myriad of redox-active cofactors as well as redox-active proteins that participate within various electron-transfer pathways in and through a cell. However, unveiling the detailed mechanism of the probe activation is outside the focus of the current study, and could be a subject of future investigation.