Armed with learnings and successes from our previous structure-guided design campaign to develop VHL ligands starting from hydroxyproline as the PTM-recognition unit, we hypothesized that small-molecule SOCS2 ligands could be rationally designed using phosphotyrosine as a suitable starting point anchor fragment for binding to the SH2 domain and disrupt the SOCS2-substrate interaction. Phosphotyrosine and its capped analogue 1 bound to SOCS2 with surprisingly high binding affinity, each with KD = 190 μM, respectively, as measured by isothermal titration calorimetry (ITC) . While this corresponded to 100-fold weaker binding than the full phosphorylated peptide, the small fragment-like size of these ligands corresponds to a ligand efficiency LE of 0.29 kcal/mol/NHA, which is excellent for targeting a PPI binding site, and so was deemed attractive to elect pY as the anchor fragment starting point. To increase the affinity, we sought to build the molecule from both the N-and C-terminal end of the pY fragment to explore interactions around the pY pocket of the SH2 domain.