Tandem mass spectrometry of small-molecule signal transduction inhibitors: Accurate-m/z data to adapt structure proposals of product ions

Abstract

Protein kinases inhibitors or, more generally, signal transduction inhibitors (STIs) can be used to treat diseases in which deregulation of the protein kinase activity plays a role, such as in cancer. A wide variety of drugs has been developed and/or is under investigation to act as protein kinase inhibitors, especially in tyrosine kinase inhibition. The bioanalysis of STIs has received considerable attention in the past 20 years. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) in selected-reaction monitoring (SRM) mode is the method-of-choice in such studies. In several of these studies from us and others, structures are proposed for the product ions applied in SRM. A critical review of these proposed structures is presented using accurate-m/z data, which we have now generated with a linear-ion-trap-Orbitrap hybrid mass spectrometer. This led to adaptation and new structural proposals of 18 product ions for 13 STIs. Our investigation endorses the power of accurate-m/z analysis in structure elucidation of product ions in bioanalytical LC-MS-MS studies and for which the SRM mode in tandem-quadrupole instruments is apparently less suitable.

Keywords: Accurate-m/z analysis; Bioanalysis; Liquid chromatography–tandem mass spectrometry; Protein kinase inhibitors; Selected-reaction monitoring; Structural analysis of product ions.