Pyridine-based small molecule inhibitors of SARM1 alleviate cell death caused by NADase activity

被引：0
|
作者：
Tang, Qingxuan [1 ,2 ,3 ,4 ,5 ]
Yin, Hang [1 ,2 ,3 ,4 ,5 ]
机构：
[1] Tsinghua Univ, State Key Lab Membrane Biol, Beijing 100084, Peoples R China
[2] Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China
[3] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China
[4] Tsinghua Univ, Minist Educ, Key Lab Bioorgan Phosphorous Chem & Chem Biol, Beijing 100084, Peoples R China
[5] Peking Univ, Tsinghua Univ, Natl Inst Biol Sci Joint Grad Program, Beijing 100084, Peoples R China
来源：
CHEMICAL COMMUNICATIONS | 2024年 / 60卷 / 66期
基金：
中国国家自然科学基金;
关键词：
NAD(+) CLEAVAGE ACTIVITY; INJURY; ACTIVATION; DELETION; MODELS;
D O I：
10.1039/d4cc02650k
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
Our investigation has unveiled a series of pyridine-based SARM1 inhibitors, with the lead compound TH-408 exhibiting remarkable potency, achieving an IC50 value of 0.46 mu M. This exceptional inhibitory effect significantly curtailed SARM1-mediated cell death across diverse biological models. This finding highlights the promising therapeutic potential for neurodegenerative disorders by disrupting SARM1 activation and advances our understanding of molecular interventions in these complex disorders, including the regulation of NAD+ metabolism. TH-408 counters toxicity by inhibiting SARM1 activation and NAD+ depletion, offering a promising approach to cell death prevention.
引用
收藏
页码：8724 / 8727
页数：4
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