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Tozasertib analogues as inhibitors of necroptotic cell death

(2018) JOURNAL OF MEDICINAL CHEMISTRY. 61(5). p.1895-1920
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Abstract
Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.
Keywords
TUMOR-NECROSIS-FACTOR, KINASE INHIBITORS, RIP1 KINASE, POTENT AURORA, BASIS-SETS, TNF-ALPHA, IN-VIVO, APOPTOSIS, INFLAMMATION, DISCOVERY

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Citation

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Chicago
Hofmans, Sam, Lars Devisscher, Sofie Martens, Dries Van Rompaey, Kenneth Goossens, Tatyana Divert, Wim Nerinckx, et al. 2018. “Tozasertib Analogues as Inhibitors of Necroptotic Cell Death.” Journal of Medicinal Chemistry 61 (5): 1895–1920.
APA
Hofmans, S., Devisscher, L., Martens, S., Van Rompaey, D., Goossens, K., Divert, T., Nerinckx, W., et al. (2018). Tozasertib analogues as inhibitors of necroptotic cell death. JOURNAL OF MEDICINAL CHEMISTRY, 61(5), 1895–1920.
Vancouver
1.
Hofmans S, Devisscher L, Martens S, Van Rompaey D, Goossens K, Divert T, et al. Tozasertib analogues as inhibitors of necroptotic cell death. JOURNAL OF MEDICINAL CHEMISTRY. 2018;61(5):1895–920.
MLA
Hofmans, Sam, Lars Devisscher, Sofie Martens, et al. “Tozasertib Analogues as Inhibitors of Necroptotic Cell Death.” JOURNAL OF MEDICINAL CHEMISTRY 61.5 (2018): 1895–1920. Print.
@article{8558250,
  abstract     = {Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.},
  author       = {Hofmans, Sam and Devisscher, Lars and Martens, Sofie and Van Rompaey, Dries and Goossens, Kenneth and Divert, Tatyana and Nerinckx, Wim and Takahashi, Nozomi and De Winter, Hans and Van der Veken, Pieter and Goossens, Vera and Vandenabeele, Peter and Augustyns, Koen},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {TUMOR-NECROSIS-FACTOR,KINASE INHIBITORS,RIP1 KINASE,POTENT AURORA,BASIS-SETS,TNF-ALPHA,IN-VIVO,APOPTOSIS,INFLAMMATION,DISCOVERY},
  language     = {eng},
  number       = {5},
  pages        = {1895--1920},
  title        = {Tozasertib analogues as inhibitors of necroptotic cell death},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.7b01449},
  volume       = {61},
  year         = {2018},
}

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