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@article{Kallemeijn:2019:10.1016/j.chembiol.2019.03.006,
author = {Kallemeijn, W and Lueg, G and Faronato, M and Hadavizadeh, K and Goya, Grocin A and Song, O-R and Howell, M and Dinnis, C and Tate, E},
doi = {10.1016/j.chembiol.2019.03.006},
journal = {Cell Chemical Biology},
pages = {892--900},
title = {Validation and invalidation of chemical probes for the human N-myristoyltransferases},
url = {http://dx.doi.org/10.1016/j.chembiol.2019.03.006},
volume = {26},
year = {2019}
}
TY - JOUR
AB - 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.
AU - Kallemeijn,W
AU - Lueg,G
AU - Faronato,M
AU - Hadavizadeh,K
AU - Goya,Grocin A
AU - Song,O-R
AU - Howell,M
AU - Dinnis,C
AU - Tate,E
DO - 10.1016/j.chembiol.2019.03.006
EP - 900
PY - 2019///
SN - 2451-9456
SP - 892
TI - Validation and invalidation of chemical probes for the human N-myristoyltransferases
T2 - Cell Chemical Biology
UR - http://dx.doi.org/10.1016/j.chembiol.2019.03.006
UR - https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(19)30083-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2451945619300832%3Fshowall%3Dtrue
UR - http://hdl.handle.net/10044/1/68674
VL - 26
ER -
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