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

TY - JOUR

T1 - Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes

AU - Bell, Andrew S.

AU - Yu, Zhiyong

AU - Hutton, Jennie A.

AU - Wright, Megan H.

AU - Brannigan, James A.

AU - Paape, Daniel

AU - Roberts, Shirley M.

AU - Sutherell, Charlotte L.

AU - Ritzefeld, Markus

AU - Wilkinson, Anthony J.

AU - Smith, Deborah F.

AU - Leatherbarrow, Robin J.

AU - Tate, Edward W.

N1 - © 2020, The Author(s).

PY - 2020/7/23

Y1 - 2020/7/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85088488413&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.0c00570

DO - 10.1021/acs.jmedchem.0c00570

M3 - Article

C2 - 32575985

AN - SCOPUS:85088488413

SN - 0022-2623

VL - 63

SP - 7740

EP - 7765

JO - JOURNAL OF MEDICINAL CHEMISTRY

JF - JOURNAL OF MEDICINAL CHEMISTRY

IS - 14

ER -