Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis
Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none o...
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doaj-904a0ce26c294682bfaefbd73cbef5d22020-11-24T21:50:21ZengMDPI AGMolecules1420-30492018-11-012311288410.3390/molecules23112884molecules23112884Identification and Characterization of NTB451 as a Potential Inhibitor of NecroptosisEun-Jung In0Yuno Lee1Sushruta Koppula2Tae-Yeon Kim3Jun-Hyuk Han4Kwang-Ho Lee5Tae-Bong Kang6BK21PLUS Glocal Education Program of Nutraceuticals Development, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, KoreaKorea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaDepartment of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, 268 Chungwon-daero, Chungju 27478, KoreaBK21PLUS Glocal Education Program of Nutraceuticals Development, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, KoreaBK21PLUS Glocal Education Program of Nutraceuticals Development, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, KoreaBK21PLUS Glocal Education Program of Nutraceuticals Development, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, KoreaDepartment of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, 268 Chungwon-daero, Chungju 27478, KoreaNecroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-<i>N</i>-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death.https://www.mdpi.com/1420-3049/23/11/2884necroptosisinhibitorNTB451RIPK1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eun-Jung In Yuno Lee Sushruta Koppula Tae-Yeon Kim Jun-Hyuk Han Kwang-Ho Lee Tae-Bong Kang |
spellingShingle |
Eun-Jung In Yuno Lee Sushruta Koppula Tae-Yeon Kim Jun-Hyuk Han Kwang-Ho Lee Tae-Bong Kang Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis Molecules necroptosis inhibitor NTB451 RIPK1 |
author_facet |
Eun-Jung In Yuno Lee Sushruta Koppula Tae-Yeon Kim Jun-Hyuk Han Kwang-Ho Lee Tae-Bong Kang |
author_sort |
Eun-Jung In |
title |
Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis |
title_short |
Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis |
title_full |
Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis |
title_fullStr |
Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis |
title_full_unstemmed |
Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis |
title_sort |
identification and characterization of ntb451 as a potential inhibitor of necroptosis |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2018-11-01 |
description |
Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-<i>N</i>-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death. |
topic |
necroptosis inhibitor NTB451 RIPK1 |
url |
https://www.mdpi.com/1420-3049/23/11/2884 |
work_keys_str_mv |
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