更新于：2024-09-19

JNK3

更新于：2024-09-19

基本信息

别名

有丝分裂原激活蛋白激酶10、c-Jun N-terminal kinase 3、JNK3

+ [12]

简介

Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the amyloid-beta precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (PubMed:22327296).

关联

项与 JNK3 相关的药物

Necrostatin-21

靶点

JNK3 x RIPK1

作用机制

JNK3抑制剂 [+1]

在研机构

中国科学院上海有机化学研究所

原研机构

中国科学院上海有机化学研究所

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

FMU200

靶点

JNK3

作用机制

JNK3抑制剂

在研机构

Universidade Do Vale Do Taquari

原研机构

Universidade Do Vale Do Taquari

在研适应症

神经系统变性病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

J30-8

靶点

JNK3

作用机制

JNK3抑制剂

在研机构

北京大学

原研机构

北京大学

在研适应症

神经系统变性病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 JNK3 相关的临床结果

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100 项与 JNK3 相关的转化医学

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0 项与 JNK3 相关的专利（医药）

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694

项与 JNK3 相关的文献（医药）

2024-12-31·Cell Adhesion & Migration

JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties

Review

作者: Xiao, Zhicheng ; Guan, Ziman ; Zhao, Yiling ; Kuriakose, Diji ; Wu, Yibeini ; Esmaeili, Sajjad

The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.

2024-10-01·Neurochemistry International

The selective disruption of the JNK2/Syntaxin-1A interaction by JGRi1 protects against NMDA-evoked toxicity in SH-SY5Y cells

Article

作者: Cimino, M ; Feligioni, M

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets. We previously reported non-conventional intracellular signaling triggered by which, upon activation, promotes the interaction between JNK2 and STX1A which enhances the rate of vesicular secretion. We developed a cell-permeable peptide, named JGRi1, able to disrupt such interaction, thus reducing vesicular secretion. In this work, to selectively study the effect of JGRi1 in a much simpler system, we employed neuroblastoma cells, SH-SY5Y. We found that SH-SY5Y cells express the components of the NMDA receptor-JNK2 axis and that the NMDA stimulus increases the rate of vesicle release. Both JGRi1 and memantine protected SH-SY5Y cells from NMDA toxicity, but only JGRi1 reduced the interaction between JNK2 and STX1A. Both drugs successfully reduced NMDA-induced vesicle release, although, unlike memantine, JGRi1 did not prevent calcium influx. NMDA treatment induced JNK2 expression, but not JNK1 or JNK3, which was prevented by both JGRi1 and memantine, suggesting that JNK2 may be specifically involved in the response to NMDA. In conclusion, being JGRi1 able to protect cells against NMDA toxicity by interfering with JNK2/STX1A interaction, it could be considered a novel pharmacological tool to counteract excitotoxicity.

2024-10-01·Science of The Total Environment

c-Jun N-terminal kinase 1/P53 signaling mediates intrinsic apoptosis of largemouth bass (Micropterus salmoides) hepatocytes under heat stress

Article

作者: Lin, Zijie ; Cai, Zhiying ; Wei, Yekai ; Ling, Qufei ; Li, Lingling

The increasing frequency of high-temperature extremes threatens largemouth bass Micropterus salmoides, a significant fish for freshwater ecosystems and aquaculture. Our previous studies at the transcript level suggested that heat stress induces hepatic apoptosis in largemouth bass. In the current study, we sought to validate these findings and further investigate the role of the c-Jun N-terminal kinase (JNK)/P53 signaling in hepatic apoptosis under heat stress. First, heat treatments were conducted in vivo and in vitro under different temperatures: 28 °C, 32 °C, and 37 °C. In primary hepatocytes subjected to heat treatment, cell viability was evaluated via the Cell Counting Kit-8, while mitochondrial membrane potential and nuclear morphology were assessed through JC-1 and Hoechst 33258 staining, respectively. We observed reductions in both cell viability and mitochondrial membrane potential (ΔΨm), along with alterations in nuclear morphology, in primary hepatocytes exposed to heat stress at temperatures of 32 °C and 37 °C. Quantitative real-time PCR revealed significant alterations in the expression profiles of intrinsic apoptosis-related genes within liver tissues under heat stress. Immunohistochemistry analysis revealed that JNK1 signaling increased as the temperature increased, JNK2 expression increased only at 37 °C, and JNK3 expression did not change with temperature. We speculate that JNK1 and JNK2 have pro- and anti-apoptotic effects, respectively. Western blot analysis conducted on cultured hepatocytes further validated these findings. JNK inhibition reduced hepatocyte apoptosis, improved nuclear morphology, and maintained ΔΨm even after 37 °C treatment. These results not only confirm that heat stress led to intrinsic apoptosis of hepatocytes but also indicated that JNK1 could mediate P53 expression and activate caspase-dependent intrinsic apoptosis in largemouth bass hepatocytes under such conditions. This study illuminates the physiological responses of largemouth bass to acute heat stress, offering valuable insights into the potential impacts of climate change on freshwater fishes and the sustainability of aquaculture.

项与 JNK3 相关的新闻（医药）

2024-05-30

·精准药物

药物筛选中心（暨南大学）对外提供新药筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、COX、GPCR、报告基因、病毒、细菌等筛选模型，能够开展肿瘤、神经系统疾病、心脑血管病、糖尿病、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）蛋白水平：激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK。蛋白酶：MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MMP-14, ADAM5, ADAM10, ADAMTS13, TACE/ADAM17, Furin, Cathepsin E, Cathepsin D, BACE-1, DDP4, DDP8, DDP9, HIV protease-1, PMVII，PMVIV。HDACs：HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6。2）肿瘤细胞活性：近500种肿瘤细胞系；基于Ba/F3的耐药模型3）抗病毒/菌药物筛选：EV71和HSV病毒活性筛选模型；金黄色葡萄球菌、大肠杆菌和沙门氏杆菌等4）体内药效：移植瘤模型对外服务1）体外活性筛选（单剂量抑制率；多剂量IC50）；2）体内药效；3）机制研究；4）药代动力学研究；5）化合物工艺优化、大量订制。咨询合作

临床1期

2024-03-21

·精准药物

药物筛选中心对外提供药物活性筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、病毒、细菌等筛选模型，能够开展肿瘤、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK……2）肿瘤细胞模型：近500种肿瘤细胞系和基于Ba/F3的耐药模型。细胞系模型（300种）包括肺癌、胰腺癌、胃癌、肝癌、白血病等肿瘤；Ba/F3模型（200种）包括ABL、EGFR、FGFR、RET、ALK、FLT3、KIT、KRAS等靶点的敏感和耐药模型（支持了5个分子进入临床研究）。3）肿瘤移植瘤模型对外服务1）蛋白和细胞活性；2）体内抗肿瘤药效；3）蛋白表达、小分子-蛋白共晶；4）药代动力学；5）基于化学蛋白质组学的靶标发现;6) 肿瘤靶标及其候选药物的成药性评估。咨询合作