Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies

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.

Keywords: CYP3A4; drug interaction; high-throughput; kinase inhibitor; molecular docking; toxicity.