Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation.
Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation.
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表型筛选确定了一种新的恶唑酮类药物，用于治疗坏死性下垂和神经炎症。
DOI：
10.1038/s41420-018-0067-0
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发表时间：
2018
影响因子：
7
通讯作者：
Rodrigues CMP
中科院分区：
文献类型：
--
作者：
Oliveira SR;Dionísio PA;Brito H;Franco L;Rodrigues CAB;Guedes RC;Afonso CAM;Amaral JD;Rodrigues CMP
Necroptosis is a regulated form of necrosis, which may be critical in the pathogenesis of neurodegenerative diseases. Neuroinflammation, characterized by the activation of glial cells such as microglia, is closely linked with neurodegenerative pathways and constitutes a major mechanism of neural damage and disease progression. Importantly, inhibition of necroptosis results in disease improvement, unveiling an alternative approach for therapeutic intervention. In the present study, we screened a small library of new molecules, potentially inhibitors of necroptosis, using two cellular models of necroptosis. A new oxazolone, Oxa12, reduced tumour necrosis factor α (TNF-α)-induced necroptosis in mouse L929 fibrosarcoma cells. Notably, Oxa12 strongly inhibited zVAD-fmk-induced necroptosis in murine BV2 microglial cells. Moreover, Oxa12 blocked phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and interfered with necrosome complex formation, indicating that Oxa12 targets components upstream of MLKL. In fact, in silico molecular docking studies revealed that Oxa12 is occupying a region similar to the 1-aminoisoquinoline type II kinase inhibitor inside the receptor-interacting protein 1 (RIP1) kinase domain. Finally, in microglial cells, Oxa12 attenuated zVAD-fmk- and lipopolysaccharide (LPS)-induced inflammatory processes, as revealed by a marked decrease of TNF-α and/or IL-1β expression. More specifically, Oxa12 negatively targeted c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, as well as NF-κB activation. Overall, we identified a strong lead inhibitor of necroptosis that is also effective at reducing inflammation-associated events. Oxa12 is a promising candidate molecule for further development to target disease states dependent on RIP kinase activity.
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影响因子：
3.7
作者：
McNamara CR;Ahuja R;Osafo-Addo AD;Barrows D;Kettenbach A;Skidan I;Teng X;Cuny GD;Gerber S;Degterev A
通讯作者：
Degterev A
影响因子：
9
作者：
通讯作者：
--
影响因子：
16
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
通讯作者：
Kaiser WJ
Akt 和 mTOR 介导神经元程序性坏死
影响因子：
9
作者：
通讯作者：
--
影响因子：
39.3
作者：
Liu T;Zhang L;Joo D;Sun SC
通讯作者：
Sun SC