TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition

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

doi:10.1080/14756366.2021.2000404

TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition

J Enzyme Inhib Med Chem. 2022 Dec;37(1):269-279. doi: 10.1080/14756366.2021.2000404.

Authors

Seulgi Lee¹, Bernie Byeonghoon Park², Hongmok Kwon², Vitchan Kim³, Jang Su Jeon⁴, Rowoon Lee³, Milan Subedi², Taehyeong Lim², Hyunsoo Ha², Dongju An¹, Jaehoon Kim¹, Donghak Kim³, Sang Kyum Kim⁴, Seyun Kim^{1

5}, Youngjoo Byun^{1

6}

Affiliations

¹ Department of Biological Sciences, KAIST, Daejeon, South Korea.
² College of Pharmacy, Korea University, Sejong, South Korea.
³ Department of Biological Sciences, Konkuk University, Seoul, South Korea.
⁴ College of Pharmacy, Chungnam National University, Daejeon, South Korea.
⁵ KAIST Institute for the BioCentury, KAIST, Daejeon, South Korea.
⁶ Biomedical Research Center, Korea University Guro Hospital, Seoul, South Korea.

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.

Keywords: Inositol hexakisphosphate kinase; cytochrome P450 3A4; structure-activity relationship.

MeSH terms

Cytochrome P-450 CYP3A / metabolism*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Phosphotransferases (Phosphate Group Acceptor) / antagonists & inhibitors*
Phosphotransferases (Phosphate Group Acceptor) / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Phosphotransferases (Phosphate Group Acceptor)
inositol hexakisphosphate kinase

Grants and funding

This work was supported by National Research Foundation of Korea (2019R1A6A1A03031807 to Y.B, 2020R1A2C3005765 and 2018R1A5A1024261 to S.K, 2021R1A2C2004696 to S.K.K.).