Very few selective inhibitors of the zeta-chain associated protein kinase 70 kDa (ZAP70) have been reported despite its importance in autoimmune diseases. Here, to induce a fit of the so-called gatekeeper residue (Met414) and hydrophobic pocket next to it, a potent Janus kinase 2 (JAK2) inhibitor was first docked into the ATP binding site of ZAP70 by structural alignment of the kinase domains. The resulting model of the complex between ZAP70 and the JAK2 inhibitor was then relaxed by an explicit solvent molecular dynamics simulation with restraints on the backbone atoms. High-throughput docking into the induced-fit conformation of ZAP70 generated by molecular dynamics has revealed 10 low-μM inhibitors which correspond to six distinct chemotypes. One of these ZAP70 inhibitors has an IC50 of 110 nM for JAK2.