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Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes

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Title: Novel thienopyrimidine inhibitors of Leishmania N-myristoyltransferase with on-target activity in intracellular amastigotes
Authors: Bell, AS
Yu, Z
Hutton, JA
Wright, MH
Brannigan, JA
Paape, D
Roberts, SM
Sutherell, CL
Ritzefeld, M
Wilkinson, AJ
Smith, DF
Leatherbarrow, R
Tate, EW
Item Type: Journal Article
Abstract: 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.
Issue Date: 23-Jul-2020
Date of Acceptance: 24-Jun-2020
URI: http://hdl.handle.net/10044/1/80204
DOI: 10.1021/acs.jmedchem.0c00570
ISSN: 0022-2623
Publisher: American Chemical Society (ACS)
Start Page: 7740
End Page: 7765
Journal / Book Title: Journal of Medicinal Chemistry
Volume: 14
Issue: 14
Copyright Statement: © 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 087792/B/08/Z
Keywords: Medicinal & Biomolecular Chemistry
0304 Medicinal and Biomolecular Chemistry
0305 Organic Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Article Number: acs.jmedchem.0c00570
Online Publication Date: 2020-06-24
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences

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