An attractive class of targets containing SH2 domains that have remained unliganded to date are the suppressor of cytokine signalling (SOCS) family of proteins. SOCS proteins can modulate cytokine signalling pathways by inhibiting the Janus kinases (JAKs) directly. In addition, because many SOCS proteins can form part of Cullin 5 E3 ligase complexes, SOCS proteins can inhibit the JAK/STAT pathway indirectly by targeting signalling components such as the cytokine receptors for ubiquitination and subsequent proteasomal degradation . Eight family members are known, SOCS1-7 and cytokine inducible SH2 containing protein (CISH), that share a conserved domain architecture with the SH2 domain functioning as the substrate adaptor mediating binding to phosphorylated partner proteins. We have been particularly interested in SOCS2 because of its role in suppressing signalling by a variety of stimuli, including growth hormone, erythropoietin, prolactin and interleukin, and due to its links to disorders of the immune system, central nervous system and cancer . In addition to its suppressive role, SOCS2 is unique within the SOCS protein family in its capability to potentiate rather than suppressing signalling, by antagonizing SOCS1 and SOCS3 activity . SOCS2 can tightly bind to adaptor subunits ElonginB/C and scaffold subunit Cullin 5 and RING domain protein Rbx2, to function as substrate receptor of Cullin 5 RING E3 ligase complex CRL5 SOCS2 . Ubiquitin E3 ligases drive the selectivity of the ubiquitin-proteasome system (UPS) by recognizing and targeting substrate proteins for ubiquitination . Drug discovery efforts targeting E3 ligases thus offer a selective mode of therapeutic intervention . A number of small molecules targeting the substrate adaptors of Cullin RING E3 ligases have been discovered, notably for the CRL2 von Hippel-Lindau (VHL) protein, for the CRL4 cereblon (CRBN) and DCAF15, and for the CRL3 Keap1 . These compounds have utility as chemical probes, either as inhibitors of the specific E3-substrate interaction to block substrate ubiquitination or degradation, or molecular glues to stabilize recruitment of neo-substrate proteins, such as the case of thalidomide and other immunomodulatory drugs with CRBN, and aryl-sulfonamides drugs with DCAF15. In addition, such E3 ligase ligands can be successfully incorporated into proteolysis targeting chimeric molecules (PROTACs) to induce degradation of proteins of interest, with the most popularly used being the VHL and CRBN ligands. The limited numbers of small-molecule E3 ligands being efficiently used for PROTACs have motivated efforts to expand the E3 handle toolbox to diversify the hijacked E3 biology, opening opportunities to enable tissue/disease specific targeting and addressing resistance mechanism currently emerging with VHL and CRBN PROTACs .