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

Andrew S. Bell, Zhiyong Yu, Jennie A. Hutton, Megan H. Wright, James A. Brannigan, Daniel Paape, Shirley M. Roberts, Charlotte L. Sutherell, Markus Ritzefeld, Anthony J. Wilkinson, Deborah F. Smith, Robin J. Leatherbarrow, Edward W. Tate

Research output: Contribution to journalArticlepeer-review


The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-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 Leishmania 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 Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.

Original languageEnglish
Pages (from-to)7740-7765
Number of pages26
Issue number14
Early online date24 Jun 2020
Publication statusPublished - 23 Jul 2020

Bibliographical note

© 2020, The Author(s).

Cite this