更新于：2024-11-01

LRRK2 x ASK1

更新于：2024-11-01

基本信息

关联

项与 LRRK2 x ASK1 相关的药物

SRT-055

靶点

ASK1 x LRRK2

作用机制

ASK1抑制剂 [+1]

在研机构

Seal Rock Therapeutics, Inc.初创企业

原研机构

Seal Rock Therapeutics, Inc.初创企业

在研适应症

肌萎缩侧索硬化 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 LRRK2 x ASK1 相关的临床结果

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100 项与 LRRK2 x ASK1 相关的转化医学

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0 项与 LRRK2 x ASK1 相关的专利（医药）

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项与 LRRK2 x ASK1 相关的文献（医药）

2017-12-01·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research3区 · 生物学

LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death

3区 · 生物学

Article

作者: Kahle, Philipp J ; Lee, Hye-Jin ; Kim, Mi-Yeon ; Lee, Young Chul ; Seol, Wongi ; Mo, Jung-Soon ; Yarmoluk, Sergiy M ; Gasser, Thomas ; Yoon, Ji-Hye ; Ann, Eun-Jung ; Ahn, Ji-Seon ; Park, Hee-Sae ; Jo, Eun-Hye ; Belmonte, Juan Carlos Izpisua ; Liu, Guang-Hui

Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD). Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site. Moreover, results of binding and kinase assays showed that LRRK2 acted as a scaffolding protein by interacting with each components of the ASK1-MKK3/6-p38 MAPK pathway through its specific domains and increasing the proximity to downstream targets. Furthermore, LRRK2-induced apoptosis was suppressed by ASK1 inhibition in neuronal stem cells derived from patients with PD. These results clearly indicate that LRRK2 acts as an upstream kinase in the ASK1 pathway and plays an important role in the pathogenesis of PD.

2009-12-01·Current Pharmaceutical Design4区 · 医学

Kinase Inhibitors as Potential Therapeutics for Acute and Chronic Neurodegenerative Conditions

4区 · 医学

Review

作者: Cuny, G D

Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKC, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.