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Citation

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}
}
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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  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821