Interest in covalent inhibitors has seen a resurgence in recent years, owing in large part to proteomics technol. to assess selectivity and de-risk off-target concerns. We have utilized our proteomics platform to guide the development of a screening library containing small mols. armed with covalent reactive groups. From these efforts we have discovered inhibitors of Janus kinase 1 (JAK1) that potently and selectively inhibit JAK1 mediated cytokine signaling through a novel allosteric pocket on the pseudokinase domain, distinct from the pocket bound by recent clin. stage inhibitors of the related kinase Tyk2. We demonstrate that our inhibitors function via inhibiting trans-phosphorylation of JAK1 via its heterodimeric JAK family member, a key step in the signalling cascade. These covalent, allosteric JAK1 inhibitors avoid the selectivity issues common to traditional kinase inhibitors, which bind to highly conserved kinase active sites. Moreover, since the target cysteine in JAK1 is not highly conserved, they have the potential to avoid potential clin. safety issues associated with inhibiting off targets such as JAK2. Herein we present the discovery and characterization of novel allosteric JAK1 inhibitors.