Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 37, Issue 1, Pages 269-279Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2021.2000404
Keywords
Inositol hexakisphosphate kinase; structure-activity relationship
Funding
- National Research Foundation of Korea [2019R1A6A1A03031807, 2020R1A2C3005765, 2018R1A5A1024261, 2021R1A2C2004696]
- National Research Foundation of Korea [2018R1A5A1024261, 2021R1A2C2004696, 2020R1A2C3005765] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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This study confirmed that TNP selectively inhibits CYP3A4 in type I binding mode. By designing and synthesising TNP analogs and conducting biochemical studies, compound 9 was found to dramatically reduce CYP3A4 inhibition while retaining IP6K-inhibitory activity.
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 (N (2)-(m-trifluorobenzyl), N (6)-(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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