Journal
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
Volume 188, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jpba.2020.113400
Keywords
SMU-B; Metabolism; Liver microsomes; CYP3A4/5; Molecular docking
Categories
Funding
- National NaturalScience Foundation of China [81573263]
- Scienceand Technology Planning Project of Guangdong Province, China [2014A020210012]
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A novel small molecule tyrosine kinase inhibitor 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (SMU-B) had good activity against ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) targets in non-small-cell lung cancer. The excellent bioactivity of SMU-B highlights the importance of determining its metabolic traits, which could provide meaningful information for further pharmacokinetic studies of SMU-B. In this work, we studied the metabolism of SMU-B in human liver microsomes. Three metabolites of SMU-B were identified by a quadrupole-time of flight tandem mass spectrometer (Q-TOF-MS), and the metabolic pathways of SMU-B were demethylation, dehydrogenation and oxidation. CYP3A4/5 was the principal isoform involved in SMU-B metabolism, as shown by chemical inhibition and recombination human enzyme studies. Additionally, a predication with a molecular docking model confirmed that SMU-B could interact with the active sites of CYP3A4 and CYP3A5. This study illuminates the metabolic profile of the anti-tumor drug SMU-B, which will accelerate its clinical use. (C) 2020 Elsevier B.V. All rights reserved.
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