Small-molecule inhibitor (SMI) of the yeast PITP Sec14 (IC50 values of 211 nM and 2.87 μM for Sec14 mediated [3H]PtdIns transfer in vitro, and Sec14 dependent cell growth inhibition of WT (CTY182, gray) strains, respectively). SMI481 (aka 6748-481 ) is a water-soluble bioactive compound exhibiting exquisite pathway selectivity in inhibiting phosphoinositide signaling in cells with >200-fold selectivity over other yeast Sec14-like transfer activities. PITP-​directed SMIs offer new and generally applicable avenues for intervening with phosphoinositide signaling pathways with selectivities superior to those afforded by contemporary lipid kinase-​directed strategies.