Previous work from us and others solved crystal structures of the unbound SOCS2-ElonginB-ElonginC (SBC) complex and characterized low nanomolar binding affinities between SBC and Cullin5, as measured using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) . We later showed using pull-down experiments with phosphorylated growth hormone receptor (GHR) peptides that the bound SOCS2 protein eluted together with all the expected subunits part of the CRL5 ligase complex, and we fully characterized the structural assembly of the CRL5 SOCS2 complex in solution . More recently, our laboratory revealed structural insights into the SOCS2-substrates interactions by solving co-crystal structures of SBC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) and erythropoietin receptor (EpoR-pY426) . The structures revealed canonical SH2 domain -substrate interactions around the key phosphotyrosine (pY) residue, and mainly backbone-directed interactions with the residues surrounding pY. The phosphate group of pY of substrate peptides is crucial for SOCS2 binding, as exemplified by the binding affinity of GHR-pY595 peptide (KD = 1.1 μM) that is completely abrogated with a non-phosphorylated analogue GHR-Y595 . Cocrystal structures revealed that the phosphate group forms key interactions with the SH2 domain of SOCS2, via a network of direct and water-mediated hydrogen bonds . Despite the potential therapeutic utility of ligands targeting the SOCS proteins, efforts have largely been limited by aforementioned challenges involved with targeting the SH2 domain. Here, we describe the structure-guided design, using fragment-based growing, of a pY-based covalent small molecule binder targeting the SOCS2 SH2 domain. A co-crystal structure with one of our high-affinity analogues serendipitously identified modification of Cys111 on SOCS2, that we later rationally exploited via chloroacetamide electrophilic substitution, yielding covalent inhibitor MN551. Site-selectivity and efficiency of covalent MN551 was evidenced by cocrystal structures and further characterised in vitro using both intact electrospray ionisation mass spectrometry and a fluorescence polarization assay. To circumvent lack of cell permeability of the naked pY group, we pursued a prodrug approach to mask the negative charge of the phosphate group. We developed a split-NanoLuc based assay and applied it to demonstrate cellular target engagement of SOCS2 and to identify the pivaloyloxymethyl (POM) moiety as best prodrug strategy, and showed rapid prodrug unmasking of our POM-protected inhibitor MN714 using in-cell F-NMR spectroscopy. We further evidence that our SOCS2 inhibitor competitively block recruitment of cellular SOCS2 protein to its native substrates via covalently modifying Cys111 using peptide-pulldown and mass spectrometry proteomics.