Study of Abl1 tyrosine kinase inhibitors by liquid chromatography-electrospray ionization-mass spectrometry

Abstract

A method to study Abl1 tyrosine kinase inhibitors (TKIs) by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was developed and validated. Chromatographic separation was achieved on a Symmetry(®) C-18 column using a gradient. The detection was performed by selected ion monitoring (SIM) mode via positive ESI interface. The limit of quantification (LOQ) was 40.8 nM for p-Abltide [product, KKGEAIpYAAPFA-NH2] and 26.7 nM for Abltide (substrate, KKGEAIYAAPFA-NH2). The residual plot of linearity calibration curve indicated a good fit with a linear model. Intra- and inter-day precision was less than 10% and accuracy was from -6.93% to +0.15%. Matrix effect was not significant in this method. The validated method was applied to an Abl1 TKIs study. Imatinib mesylate (IM) and dasatinib were used to evaluate this method and the IC50 values were 202.1 nM and 925.1 pM, respectively. Two natural products (-)- epigallocatechingallate (EGCG) and caffeic acid were tested with this model. The IC50 value of EGCG was found at 64.03 nM and caffeic acid showed fluctuant inhibitory activity from 26% to 55% in the concentration range from 1 nM to 1mM. The IC50 value of a dimethylpyrrole hydroxylbenzoic acid derivative (MPB) was 1.915 μM.