From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors

被引：18

作者：

Gardner, Christopher R. ^{[1
,2
]}

Davies, Katherine A. ^{[1
,2
]}

Zhang, Ying ^{[1
,2
]}

Brzozowski, Martin ^{[1
,2
,3
]}

Czabotar, Peter E. ^{[1
,2
]}

Murphy, James M. ^{[1
,2
]}

Lessene, Guillaume ^{[1
,2
,4
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Parkville, VIC 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, VIC 3052, Australia

[3] Bio21 Inst, 30 Flemington Rd, Parkville, VIC 3052, Australia

[4] Univ Melbourne, Dept Pharmacol & Therapeut, Parkville, VIC 3052, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 04期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

MIXED-LINEAGE KINASE; DOMAIN-LIKE PROTEIN; CELL-DEATH; PSEUDOKINASE MLKL; HIGHLY POTENT; CHEMICAL INHIBITOR; CASPASE INHIBITOR; DISTINCT ROLES; DISCOVERY; RIPK3;

D O I：

10.1021/acs.jmedchem.2c01621

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Necroptosis is a regulated caspase-independent form of necrotic cell death that results in an inflammatory phenotype. This process contributes profoundly to the pathophysiology of numerous neurodegenerative, cardiovascular, infectious, malignant, and inflammatory diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and the mixed lineage kinase domain-like protein (MLKL) pseudokinase have been identified as the key components of necroptosis signaling and are the most promising targets for therapeutic intervention. Here, we review recent developments in the field of small-molecule inhibitors of necroptosis signaling, provide guidelines for their use as chemical probes to study necroptosis, and assess the therapeutic challenges and opportunities of such inhibitors in the treatment of a range of clinical indications.

引用

页码：2361 / 2385

页数：25

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