TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition |
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| Authors: | Seulgi Lee Bernie Byeonghoon Park Hongmok Kwon Vitchan Kim Jang Su Jeon Rowoon Lee Milan Subedi Taehyeong Lim Hyunsoo Ha Dongju An Jaehoon Kim Donghak Kim Sang Kyum Kim Seyun Kim Youngjoo Byun |
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| Affiliation: | aDepartment of Biological Sciences, KAIST, Daejeon, South Korea;bCollege of Pharmacy, Korea University, Sejong, South Korea;cDepartment of Biological Sciences, Konkuk University, Seoul, South Korea;dCollege of Pharmacy, Chungnam National University, Daejeon, South Korea;eKAIST Institute for the BioCentury, KAIST, Daejeon, South Korea;fBiomedical Research Center, Korea University Guro Hospital, Seoul, South Korea |
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| Abstract: | Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors. |
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| Keywords: | Inositol hexakisphosphate kinase cytochrome P450 3A4 structure-activity relationship |
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