Novel Thienopyrimidine Inhibitors of -Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.

The leishmaniases, caused by species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. -Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (), a compound with modest activity against intracellular amastigotes and excellent selectivity (>660-fold) for NMT over human NMTs.