Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies |
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Authors: | Zhi‐Xin Wang Jiazhi Sun Caitlin E Howell Qing‐Yu Zhou Zhi‐Xu He Tianxin Yang Helen Chew Wei Duan Zhi‐Wei Zhou Jagat R Kanwar Shu‐Feng Zhou |
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Institution: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, , Tampa, FL, 33612 USA;2. Guizhou Provincial Key Lab for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino‐US Joint Laboratory for Medical Sciences, Guiyang Medical University, , Guiyang, 550004 Guizhou, China;3. Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, , Salt Lake City, UT, 84132 USA;4. School of Medicine, Deakin University, , Waurn Ponds, Victoria, 3217 Australia;5. Nanomedicine Laboratory of Immunology and Molecular Biomedical Research (LIMBR), School of Medicine, Deakin University, , Waurn Ponds, Victoria, 3217 Australia |
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Abstract: | Kinase inhibitors (KIs) represent an important group of anticancer drugs, and many of them are substrates and inhibitors of human cytochrome P450s (CYPs), raising the potential of harmful drug interactions. This study investigated the effect of a library of KIs (n = 91) including 11 FDA‐approved KIs on human CYP1A2, 2D6, 2C9, and 3A4 using high‐throughput screening kits and the binding modes with CYPs using the Discovery Studio program 3.1. The KIs exhibited differential inhibitory effect on CYP1A2, 2D6, 2C9, and 3A4, while some of them showed activating effect on CYP2C9 and 3A4. For example, SP 600125 was a potent inhibitor for CYP1A2, but enhanced the activity of CYP2C9 fourfolds. Among the 80 KIs that are not used clinically, about 13% showed significant inhibition to CYPs. Nilotinib, sunitinib, and imatinib were found to be potent CYP1A2 inhibitor. Our docking studies have demonstrated the importance of multiple amino acid residues in the active sites of CYP1A2, 2C9, 2D6, and 3A4 in binding with various KIs. Finally, the in vitro data were used to predict potential KI–drug interactions. These findings indicate that many KIs can serve as CYP inhibitors, and further studies are needed to examine the clinical impact. |
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Keywords: | CYP3A4 drug interaction high‐throughput kinase inhibitor molecular docking toxicity |
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