TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition
- Authors
- Lee, Seulgi; Park, Bernie Byeonghoon; Kwon, Hongmok; Kim, Vitchan; Jeon, Jang Su; Lee, Rowoon; Subedi, Milan; Lim, Taehyeong; Ha, Hyunsoo; An, Dongju; Kim, Jaehoon; Kim, Donghak; Kim, Sang Kyum; Kim, Seyun; Byun, Youngjoo
- Issue Date
- 1-1월-2022
- Publisher
- TAYLOR & FRANCIS LTD
- Keywords
- Inositol hexakisphosphate kinase; structure-activity relationship
- Citation
- JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, v.37, no.1, pp.269 - 279
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
- Volume
- 37
- Number
- 1
- Start Page
- 269
- End Page
- 279
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/135281
- DOI
- 10.1080/14756366.2021.2000404
- ISSN
- 1475-6366
- 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 (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.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - College of Pharmacy > Department of Pharmaceutical Science > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.