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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2020.1
- 수록면
- 222 - 227 (6page)
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Inositol polyphosphate multikinase (IPMK) is required for the biosynthesis of inositol phosphates (IPs) through the phosphorylation of multiple IP metabolites such as IP3 and IP4. The biological significance of IPMK’s catalytic actions to regulate cellular signaling events such as growth and metabolism has been studied extensively. However, pharmacological reagents that inhibit IPMK have not yet been identified. We employed a structure-based virtual screening of publicly available U.S. Food and Drug Administration-approved drugs and chemicals that identified the antidepressant, vilazodone, as an IPMK inhibitor. Docking simulations and pharmacophore analyses showed that vilazodone has a higher affinity for the ATP-binding catalytic region of IPMK than ATP and we validated that vilazodone inhibits IPMK’s IP kinase activities in vitro. The incubation of vilazodone with NIH3T3-L1 fibroblasts reduced cellular levels of IP5 and other highly phosphorylated IPs without influencing IP4 levels. We further found decreased Akt phosphorylation in vilazodone-treated HCT116 cancer cells. These data clearly indicate selective cellular actions of vilazodone against IPMK-dependent catalytic steps in IP metabolism and Akt activation. Collectively, our data demonstrate vilazodone as a method to inhibit cellular IPMK, providing a valuable pharmacological agent to study and target the biological and pathological processes governed by IPMK.
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참고문헌 (27)
참고문헌 신청
Berridge, M. J. / 2000 / The versatility and universality of calcium signalling / Nat. Rev. Mol. Cell Biol 1:11~21
Chakraborty, A. / 2011 / Inositol pyrophosphates as mammalian cell signals / Sci. Signal 4:1~12
Cruz, M. P / 2012 / Vilazodone HCL(Viibryd) : a serotonin partial agonist and reuptake inhibitor for the treatment of major depressive disorder / P. T 37:28~31
Dovey, C. M. / 2018 / MLKL requires the inositol phosphate code to execute necroptosis / Mol. Cell 70:936~948
Frederick, J. P. / 2005 / An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production / Proc. Natl. Acad. Sci. U. S. A 102:8454~8459
Chakraborty, A. / 2011 / Inositol pyrophosphates as mammalian cell signals / Sci. Signal 4:1~12
Cruz, M. P / 2012 / Vilazodone HCL(Viibryd) : a serotonin partial agonist and reuptake inhibitor for the treatment of major depressive disorder / P. T 37:28~31
Dovey, C. M. / 2018 / MLKL requires the inositol phosphate code to execute necroptosis / Mol. Cell 70:936~948
Frederick, J. P. / 2005 / An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production / Proc. Natl. Acad. Sci. U. S. A 102:8454~8459
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