Pseudohypoaldosteronism type II is a rare, familial, autosomal-dominant hypertensive disease that is caused by mutations of WNK (with no lysine [K]) protein kinases 1 and 4. WNKs lack a lysine residue in β3 strand that is generally conserved in protein kinases. WNK 1 and WNK4 share 87% homology, and possess an unusual back pocket just behind the catalytic lysine residue (Lys233 in WNK1). Therefore, compounds interacting with both the back pocket and catalytic lysine residue could be selective inhibitors. Here, we screened a fragment library for inhibitors of WNK1-mediated phosphorylation by means of mobility shift assay and surface plasmon resonance (SPR)-based binding assay. Among the identified inhibitors, some interacted with the back pocket rather than the hinge region of WNK1, as determined by SPR competitive binding assay. The results of kinase profiling suggest these compounds are promising leads for development of selective inhibitors of WNK 1 and 4.