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Validation and invalidation of chemical probes for the human N-myristoyltransferases

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Title: Validation and invalidation of chemical probes for the human N-myristoyltransferases
Authors: Kallemeijn, W
Lueg, G
Faronato, M
Hadavizadeh, K
Goya Grocin, A
Song, O-R
Howell, M
Dinnis, C
Tate, E
Item Type: Journal Article
Abstract: On-target, cell-active chemical probes are of fundamental importance in both chemical and cell biology, whereas the application of poorly-characterised probes often leads to invalid conclusions.Human N-myristoyltransferase (NMT) has attracted increasing interest as a target in cancer and infectious diseases; here we report an in-depth comparison of five compounds widely applied as human NMT inhibitors, using a combination of quantitative whole-proteome N-myristoylation profiling, biochemical enzyme assays, cytotoxicity, in-cell protein synthesis and cell cycle assays. We find that N-myristoylation is unaffected by 2-hydroxymyristic acid (100 μM), D-NMAPPD (30 μM) or Tris-DBA palladium (10 μM), with the latter compounds causing cytotoxicity through mechanisms unrelated to NMT. In contrast, drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 delivered complete and specific inhibition of N-myristoylation in a range of cell lines at 1 μM and 100 nM, respectively. This study enables the selection of appropriate on-target probes for future studies and suggests the need for reassessment of previous studies which used off-target compounds.
Issue Date: 20-Jun-2019
Date of Acceptance: 6-Mar-2019
URI: http://hdl.handle.net/10044/1/68674
DOI: https://doi.org/10.1016/j.chembiol.2019.03.006
ISSN: 2451-9456
Publisher: Elsevier
Start Page: 892
End Page: 900
Journal / Book Title: Cell Chemical Biology
Volume: 26
Issue: 6
Copyright Statement: © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: The Royal Society
Cancer Research UK
Funder's Grant Number: NF161582
20183
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
TRIS DIBENZYLIDENEACETONE DIPALLADIUM
POTENTIAL-DRUG TARGET
MYRISTOYL-COA
ESSENTIAL ENZYME
DBA PALLADIUM
PROTEIN
INHIBITORS
CANCER
APOPTOSIS
DISCOVERY
2-hydroxymyristic acid
D-NMAPPD (B13)
IMP-1088
IMP-366 (DDD85646)
N-myristoylation
N-myristoyltransferases (NMT)
Tris-DBA palladium
chemical proteomics
metabolic tagging
sortase A ligation
Publication Status: Published
Online Publication Date: 2019-04-18
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences