Proteomics

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


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 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Wouter Kallemeijn  

LAB HEAD: Edward W. Tate

PROVIDER: PXD012722 | Pride | 2019-11-14

REPOSITORIES: Pride

Dataset's files

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Action DRS
MaxQuantOutput.tar.gz Other
WWK20180601-Experimentalsetup.xlsx Xlsx
wwk20180517_h1-f1.index Other
wwk20180517_h1-f1.raw Raw
wwk20180517_h1-f2.index Other
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Publications

Validation and Invalidation of Chemical Probes for the Human N-myristoyltransferases.

Kallemeijn Wouter W WW   Lueg Gregor A GA   Faronato Monica M   Hadavizadeh Kate K   Goya Grocin Andrea A   Song Ok-Ryul OR   Howell Michael M   Calado Dinis P DP   Tate Edward W EW  

Cell chemical biology 20190418 6


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,  ...[more]

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