Journal
CELL CHEMICAL BIOLOGY
Volume 26, Issue 6, Pages 892-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2019.03.006
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Funding
- Royal Society (Newton International Fellowship) [NF161582]
- European Commission (Marie Sklodowska Curie Individual Fellowship) [752165]
- MRC CDA [MR/J008060/1]
- Cancer Research UK [C29637/A21451, C29637/A20183]
- Francis Crick Institute from Cancer Research UK [FC001057, FC001097]
- UK Medical Research Council [FC001057, FC001097]
- Wellcome Trust [FC001057, FC001097]
- Marie Curie Actions (MSCA) [752165] Funding Source: Marie Curie Actions (MSCA)
- MRC [MR/J008060/1] Funding Source: UKRI
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On-target, cell-active chemical probes are of fundamental importance in chemical and cell biology, whereas poorly characterized probes often lead to invalid conclusions. Human N-myristoyltransferase (NMT) has attracted increasing interest as 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 mu M), D-NMAPPD (30 mu M), or TrisDBA palladium (10 mu M), 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 mu M 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 that used off-target compounds.
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