Drug design efforts targeting SH2 domain have historically been unsuccessful because of enzymatic lability and poor cellular permeability of the negatively charged phosphate group, and the challenges with developing phospho-mimetic ligands. Here, we describe a rational, structure-guided ligand design approach to arrive at a high-affinity cell-permeable ligand for the SH2 domain of SOCS2. There are some important points when considering tackling of the main challenges associated with targeting SH2 domains and to study SH2-domain-containing proteins. The phosphate group present in the pY-substrates is typically considered a major liability by medicinal chemists, mainly due to its double-negative charge that hampers cell permeability, and it also presents synthetic challenges 5 . Despite this, there are precedent for phosphatecontaining drugs and several therapeutic agents contain phosphates or other phosphorus-containing groups, such as fostemsavir and fosamprenavir for use in patients with HIV infections, fludarabine phosphate for the treatment of chronic lymphocytic leaukemia, and fosphenytoin in the treatment of epileptic seizures, amongst others . For the most such phosphate-containing molecules are typically designed as prodrugs to improve solubility of the parent drug, and undergo hydrolysis during the absorption and distribution process, and prior to entering the cell and reaching the target. In contrast, no pY-containing chemical probes or drugs that target specifically intracellular targets have been developed to our knowledge. In the case of pY-containing molecules, triester prodrugs strategies have been described, but have remained niche . To address the drawbacks from the poor cellular uptake of pY-containing ligands, as prodrug strategy we evaluated phosphotyrosine-masking groups. Triage of different phosphate-protecting groups allowed identification of POM as the best prodrug enabling the inhibitor to enter the cell, efficiently unmask and engage cellular SOCS2 covalently specifically via Cys111 modification. The low efficacy of aryloxy triester phosphoramidate prodrugs can be explained by the lower levels of expression of the enzymes that unmask these prodrugs in HeLa cells . The design and validation methods described in this work exemplifies a blueprint that could be in future used to develop and evaluate other pY-containing small molecules.