We utilized CETSA in a live cell mode to evaluate the efficacy and rank the different prodrugs. We treated live HeLa cells with 50 μM compound (prodrugs) for 20 hours and monitored Tagg shift as a proxy for the combo of prodrug permeability and unmasking (Figure ). Among all the prodrugs, POM protected MN551 (MN714), showed consistent superior SOCS2 engagement. The observation could be because the POM group unmasking requires only esterase unlike the reliance of compounds 21-23 on esterase and phosphoramidase for unmasking an aryloxy phosphoramidate group. Furthermore, the increased hydrophilicity of POM protected MN714 with respect to the aryloxy phosphoramidate prodrugs likely enhanced the cell-permeability. MN714 (cLogP 4.329) was significantly less lipophilic than all phosphoramidate prodrugs tested (cLogP ranging from 4.729 to 5.818), placing it firmly within the desired range for lipophilicity as outlined in Lipinski's rule of 5. Having established POM protected MN714 as the best prodrug, we demonstrated the dose-dependent cellular potency of the compound. EC50 after 2 hours and 8 hours of treatment is 3.8 μM and 2.5 μM respectively (Figure ). The compound, as expected for a covalent binder, displays a time-dependent drop in EC50 values.