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Molecules 2018, 23(11), 2884; https://doi.org/10.3390/molecules23112884

Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis

1
BK21PLUS Glocal Education Program of Nutraceuticals Development, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, Korea
2
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
3
Department of Biotechnology, College of Biomedical & Health Science, Research Institute of Inflammatory Diseases, 268 Chungwon-daero, Chungju 27478, Korea
*
Authors to whom correspondence should be addressed.
Received: 13 October 2018 / Revised: 1 November 2018 / Accepted: 4 November 2018 / Published: 5 November 2018
(This article belongs to the Section Materials Chemistry)
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Abstract

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)-N-(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. View Full-Text
Keywords: necroptosis; inhibitor; NTB451; RIPK1 necroptosis; inhibitor; NTB451; RIPK1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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In, E.-J.; Lee, Y.; Koppula, S.; Kim, T.-Y.; Han, J.-H.; Lee, K.-H.; Kang, T.-B. Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis. Molecules 2018, 23, 2884.

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