The serendipitous observation of Cys111-modification in one of the cocrystal structures solved during the course of the ligand optimization campaign was leveraged to rationally design a covalent inhibitor. Interestingly the same cysteine was identified to be reactive to several electrophiles used by Vinogradova et al., suggesting tractability of targeting this cysteine covalently . Over the last decade the view on covalent inhibitors has shifted and targeted covalent inhibition has undergone a renaissance as a promising approach in chemical biology and drug discovery, especially for targeting challenging proteins. Covalent modification of the reactive Cys111 residue by MN551 was confirmed by co-crystal structures, and intact ESI-MS spectra with recombinant protein and mutants. FP-displacement binding assay allowed determining the key kinetic parameter of covalent inhibition -namely kinact /KI. This work provides a benchmark for future optimisation strategies to improve the covalency of MN551, which will revolve around increasing kinact/KI by improving the reversible binding affinity and/or increasing the rate of reactivity of the ligand. The chemical probes could provide long awaited insight into the role of SOCS2 in regulation of growth hormone signalling and NF-kB signalling . Future work will also focus on establish the functional impact of cellular inhibition of SOCS2, and the intra-SOCS family selectivity inhibition, thereby demonstrating full application of MN551/MN714 and/or their non-covalent analogues as probes to study the JAK/STAT signalling pathway. The efficient covalent modification of recombinant CISH (66-258, Δ174-202) by MN551 justifies future biophysical, structural, and cellular characterisation to verify if the covalency translates to full length intracellular CISH. Considering the interest in inhibition of CISH as an antitumor therapeutic strategy aimed at enhancing activity of Natural Killer (NK) cells and decreasing PD-1 expression levels, chemical probes targeting selectively CISH would be of great utility .