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Leveraging Gas-Phase Fragmentation Pathways for Improved Identification and Selective Detection of Targets Modified by Covalent Probes.
- Source :
-
Analytical chemistry [Anal Chem] 2016 Dec 20; Vol. 88 (24), pp. 12248-12254. Date of Electronic Publication: 2016 Nov 30. - Publication Year :
- 2016
-
Abstract
- The recent approval of covalent inhibitors for multiple clinical indications has reignited enthusiasm for this class of drugs. As interest in covalent drugs has increased, so too has the need for analytical platforms that can leverage their mechanism-of-action to characterize modified protein targets. Here we describe novel gas phase dissociation pathways which yield predictable fragment ions during MS/MS of inhibitor-modified peptides. We find that these dissociation pathways are common to numerous cysteine-directed probes as well as the covalent drugs, Ibrutinib and Neratinib. We leverage the predictable nature of these fragment ions to improve the confidence of peptide sequence assignment in proteomic analyses and explore their potential use in selective mass spectrometry-based assays.
- Subjects :
- Adenine analogs & derivatives
Amino Acid Sequence
Cell Line, Tumor
Drug Discovery methods
Humans
Molecular Targeted Therapy
Peptides metabolism
Piperidines
Protein Kinases chemistry
Protein Kinases metabolism
Peptides analysis
Protein Kinase Inhibitors pharmacology
Proteomics methods
Pyrazoles pharmacology
Pyrimidines pharmacology
Quinolines pharmacology
Tandem Mass Spectrometry methods
Subjects
Details
- Language :
- English
- ISSN :
- 1520-6882
- Volume :
- 88
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Analytical chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28193034
- Full Text :
- https://doi.org/10.1021/acs.analchem.6b03394