BibTex format
@article{Bell:2020:10.1021/acs.jmedchem.0c00570,
author = {Bell, AS and Yu, Z and Hutton, JA and Wright, MH and Brannigan, JA and Paape, D and Roberts, SM and Sutherell, CL and Ritzefeld, M and Wilkinson, AJ and Smith, DF and Leatherbarrow, R and Tate, EW},
doi = {10.1021/acs.jmedchem.0c00570},
journal = {Journal of Medicinal Chemistry},
pages = {7740--7765},
title = {Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes},
url = {http://dx.doi.org/10.1021/acs.jmedchem.0c00570},
volume = {14},
year = {2020}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with 12-15 million 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 antileishmanial target. Here we describe a comprehensive structure activity relationship 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 L. donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.
AU - Bell,AS
AU - Yu,Z
AU - Hutton,JA
AU - Wright,MH
AU - Brannigan,JA
AU - Paape,D
AU - Roberts,SM
AU - Sutherell,CL
AU - Ritzefeld,M
AU - Wilkinson,AJ
AU - Smith,DF
AU - Leatherbarrow,R
AU - Tate,EW
DO - 10.1021/acs.jmedchem.0c00570
EP - 7765
PY - 2020///
SN - 0022-2623
SP - 7740
TI - Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes
T2 - Journal of Medicinal Chemistry
UR - http://dx.doi.org/10.1021/acs.jmedchem.0c00570
UR - https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00570
UR - http://hdl.handle.net/10044/1/80204
VL - 14
ER -
