更新于：2024-09-19

MAPKAPK3

更新于：2024-09-19

基本信息

别名

3pK、Chromosome 3p kinase、MAP kinase-activated protein kinase 3

+ [10]

简介

Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.

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100 项与 MAPKAPK3 相关的临床结果

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100 项与 MAPKAPK3 相关的转化医学

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0 项与 MAPKAPK3 相关的专利（医药）

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240

项与 MAPKAPK3 相关的文献（医药）

2024-07-01·Molecular Pharmaceutics

A Combination of Biocatalysis and Fenton-Like Reaction Induced OH^• Burst for Cascade Amplification of Cancer Chemodynamic Therapy

Article

作者: Zhang, Peng ; Xu, Wenjia ; Li, Minghui ; Liu, Sha ; Wu, Yan ; Cheng, Liying ; Li, Jinyang ; Xu, Xiaopeng ; Yang, Gangqiang ; Sun, Kaoxiang ; Wang, Min ; Qin, Yang

Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OH^•) from hydrogen peroxide (H₂O₂) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH ^• is easily scavenged by glutathione (GSH) and the intracellular H₂O₂ level is insufficient in the tumor cells. Herein, we propose the Mn²⁺-menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH^• storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H₂O₂ via redox cycling, and further the cytotoxic OH ^• burst was induced by Mn²⁺-mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.

2024-03-01·Journal of Environmental Sciences

Ethylene thiourea exposure induces neurobehavioral toxicity in zebrafish by disrupting axon growth and neuromuscular junctions

Article

作者: Chen, Yuanyao ; Zhang, Huiping ; Wang, Jingming ; Zong, Yanjun ; Wang, Yongfeng ; Feng, Qiyuan ; Yu, Zhiquan ; Peng, Lianqi ; Liu, Chunyan ; Xiao, Lin

Ethylene thiourea (ETU) converted from ethylene bisdithiocarbamate (EBDC) fungicides has aroused great concern because of its prevalence and harmful effects. Although ETU-induced neurotoxicity has been reported, the potential mechanisms remain unclear. This study provided insights into its neurotoxic effects at environmentally relevant concentrations in zebrafish. Our findings showed that embryonic exposure to ETU decreased the hatch rate and delayed somite development. Furthermore, ETU treatment significantly reduced the dark velocity in the locomotion assay. The upregulated tendency of the mitogen-activated protein kinases (MAPK) pathway (mknk1, atf4, mapkapk3) screened by transcriptome analysis implied motor neuron degeneration, which was validated by subsequent morphological observation, as axon length and branches were truncated in the 62.5 µg/L ETU group. However, although the rescue experiment with a p38 MAPK inhibitor (SB203580) successfully ameliorated axon degeneration, it failed to reverse the locomotion behaviors. Further exploration of transcriptome data revealed the varied expression of presynaptic scaffold protein-related genes (pcloa, pclob, bsna), whose downregulation might impair the neuromuscular junction (NMJ). Therefore, we reasonably suspected that ETU-induced neurobehavioral deficits might result from the combined effects of the MAPK pathway and presynaptic proteins. Considering this, we highlighted the necessity to take precautions and early interventions for susceptible ETU-exposed populations.

2023-08-05·International journal of molecular sciences

Integrated Transcriptome and Molecular Docking to Identify the Hub Superimposed Attenuation Targets of Curcumin in Breast Cancer Cells.

Article

作者: Zhang, Jing ; Yuan, Ting ; Chen, Peide ; Wang, Rui ; Yu, Hao

Numerous in vitro and in vivo studies have shown that curcumin primarily activates apoptotic pathways in cancer cells and inhibits cancer progression by modulating various molecular targets. In this study, we utilized reverse docking servers to predict 444 human proteins that may potentially be targeted by curcumin. Then, high-throughput assays were conducted by using RNA-seq technology on curcumin-treated MCF-7 (human breast cancer ER (+)) and MDA-MB-231 (human breast cancer ER(-)/TNBC) cancer cell lines. Enrichment analysis identified seven and eight significantly down-regulated signaling pathways in these two cell lines, where the enriched genes were used to construct protein-protein interaction networks. From these networks, the MCODE algorithm screened out 42 hub targets, which are core genes of the RTK-(PI3K-AKT)/(MEK/ERK1/2) crosstalk network. Genetic alteration and expression patterns of hub targets of curcumin may be closely related to the overall pathogenesis and prognosis of breast cancer. MAPKAPK3, AKT3, CDK5, IGF1R, and MAPK11 are potential prognostic markers and therapeutic targets of curcumin in patients with triple-negative breast cancer. Molecular docking and transcriptomic results confirmed that curcumin can inhibit these high-scoring targets at the protein level. Additionally, these targets can act as self-feedback factors, relying on the cascading repressive effects in the network to limit their own transcription at the mRNA level. In conclusion, the integration of transcriptomic and molecular docking approaches enables the rapid identification of dual or multiple inhibitory targets of curcumin in breast cancer. Our study provides the potential elucidation of the anti-cancer mechanism of curcumin.

项与 MAPKAPK3 相关的新闻（医药）

2022-03-26

·医药观澜

罗氏、加科思、诺诚健华、先声药业等公司新药获批临床、

根据中国国家药监局药品审评中心（CDE）官网数据，本周有20款左右1类新药（不含补充申请）的临床试验申请通过“默示许可”。经过梳理，这些1类新药包括了RAF抑制剂、TYK2 JH2变构抑制剂、PRMT5抑制剂、抗CD73单抗、抗TIGIT单抗、JAK1/2抑制剂等等。本文中，我们将挑选部分1类新药作介绍，供读者参阅。 1、罗氏（Roche）：Belvarafenib 作用机制：RAF抑制剂适应症：BRAF II类突变/融合阳性、BRAF III类突变阳性肿瘤 Belvarafenib（又称RG6185或HM95573)是罗氏与韩美公司（Hanmi Pharmaceutical）合作开发的一款抑制RAF二聚体的抑制剂，旨在抑制MAPK信号通路。RAS/MAPK信号通路的基因突变包括KRAS、NRAS和BRAF等，它们通常会驱动多种肿瘤的发生。据罗氏公司公开资料介绍，belvarafenib能够阻断RAS下游信号通路，如NRAS突变。该药目前正在海外开展针对实体瘤的1期临床研究。早期临床研究数据显示，在携带NRAS突变的黑色素瘤患者中，belvarafenib与罗氏旗下的一款小分子MEK抑制剂联用，表现出积极的疗效。本次在中国，这款RAF抑制剂获批临床的适应症为：BRAF II类突变/融合阳性、BRAF III类突变阳性肿瘤。 2、诺诚健华：ICP-488片作用机制：TYK2 JH2变构抑制剂适应症：免疫炎症性疾病 ICP-488为诺诚健华自主研发的新型口服酪氨酸激酶2（TYK2）变构抑制剂。TYK2是JAK家族成员之一，是一种介导IL-23、IL-12和I型干扰素（IFN）信号转导的细胞内信号激酶。它在传递炎症和免疫应答信号方面具有重要的作用，被认为与多种免疫介导疾病的病理相关。根据诺诚健华早先公开资料介绍，ICP-488通过作用于发挥调节作用的TYK2 JH2，阻断TYK2依赖的IL-23等炎性细胞因子驱动的细胞信号转导，从而抑制自身免疫和炎症的病理过程。本次，该药获批临床的适应症为：银屑病、特应性皮炎、银屑病关节炎、炎症性肠病和系统性红斑狼疮等免疫炎症性疾病。 3、先声药业：SCR-6920胶囊作用机制：PRMT5抑制剂适应症：晚期恶性肿瘤 SCR-6920是一款口服蛋白精氨酸甲基转移酶5（PRMT5）抑制剂，是先声药业自主研发的针对“合成致死”机制的创新抗肿瘤药物。甲硫腺苷磷酸化酶（MTAP）缺失是肿瘤中的常见突变，而PRMT5是此类肿瘤的“合成致死”靶点。据先声药业新闻稿介绍，SCR-6920具有PRMT5高抑制活性和高选择性。药代动力学研究显示，SCR-6920倾向于分布在肿瘤内，肿瘤内药物浓度与血浆药物浓度比值是其他在研PRMT5抑制剂的10倍左右，这意味着SCR-6920在获得更好抑瘤效果的同时，具有更低的血浆暴露量，可以更大程度降低靶点相关的血液毒性。据悉，本次SCR-6920获批的为一项治疗晚期恶性肿瘤的多中心1期临床研究，研究将评价该药的安全性、耐受性、有效性以及药代动力学特征。 4、加科思药业：JAB-BX102 作用机制：抗CD73单抗适应症：晚期实体瘤 JAB-BX102是加科思药业自主研发的抑制CD73酶活性的人源化单克隆抗体。CD73是肿瘤免疫疗法的新兴靶点之一，是一种催化单磷酸腺苷向腺苷转化的限速酶。CD73介导的腺苷通路是肿瘤微环境中先天性免疫和适应性免疫的关键调节剂。还有研究显示，CD73的抑制结合免疫检查点抑制剂、靶向治疗或常规治疗改善了许多临床前小鼠癌症模型的抗肿瘤效果。据加科思药业新闻稿，临床前数据表明，JAB-BX102具有剂量活性优势，有潜力使实体瘤患者获益。2021年10月，JAB-BX102在美国获批临床，拟在美国启动针对实体瘤患者的1/2a期临床试验。本次在中国，JAB-BX102获批临床的适应症为：单药或联合抗PD-1单抗帕博利珠单抗用于治疗成人晚期实体瘤，将在中国启动1期临床试验。 5、普米斯生物：PM1015 注射液作用机制：抗CD73单抗适应症：晚期实体瘤 PM1015是普米斯生物开发的人源化抗CD73单克隆抗体。据普米斯生物早先新闻稿介绍，与大多数抗CD73在研产品不同，PM1015拥有特殊的结合表位，能在多种表达CD73的肿瘤细胞系上完全阻断膜型CD73酶活性。体内药效实验表明，PM1015可以在多种小鼠肿瘤模型中有效抑制肿瘤生长，且显示出良好的剂量依赖性抗肿瘤活性。同时，PM1015在临床前毒理实验中显现出了较好的安全性和耐受性。本次，该药获批在晚期实体瘤受试者中开展临床试验。 6、康方生物：AK127注射液作用机制：抗TIGIT单抗适应症：晚期恶性肿瘤 AK127是康方生物自主研发的靶向TIGIT的新型人源化IgG1k单克隆抗体药物。抗TIGIT药物可防止T细胞免疫球蛋白和ITIM结构域（TIGIT）与其配体CD155结合，从而消除阻碍T细胞和NK细胞攻击癌症的抑制信号。此外，TIGIT表达与PD-1密切相关，尤其是在肿瘤浸润性T细胞中，这两个靶点通常在同一细胞上共表达，这为开发抗TIGIT药物联合抗PD-1/PD-L1抗体提供了科学依据。康方生物公开资料介绍，研究表明，AK127可有效地阻断TIGIT信号通路介导的免疫抑制，增强免疫细胞激活。AK127单药展现出良好的药理学活性，而与该公司的卡度尼利（PD-1/CTLA-4双抗，AK104）联用更显示了良好的协同增效效应。AK127与AK104联合治疗晚期或转移性实体瘤的1期临床试验已经于去年10月在澳大利亚完成首例患者给药。本次，AK127在中国获批临床，拟开发适应症为晚期恶性肿瘤。 7、赛默罗德生物：SR1375胶囊作用机制：神经炎性机制小分子抑制剂适应症：糖尿病性黄斑水肿 SR1375胶囊是赛默罗德生物自主研发的糖尿病性视网膜病变治疗候选药。据赛默罗德生物新闻稿介绍，这是一款神经炎性机制小分子抑制剂。它具有全新作用机制，而且可以口服给药，打破了Anti-VEGF必须经由玻璃体注射带来的临床应用限制。在动物模型中，SR1375展现了和Anti-VEGF可比的药效，有望为相应的患者提供更方便、安全、有效的用药选择。据悉，SR1375目前正在澳大利亚健康人群中开展临床1期研究，并于2021年10月完成首次临床试验中第一个剂量组给药。本次在中国，该药获批临床的适应症为糖尿病性黄斑水肿（DME）。公开资料显示，DME是糖尿病患者的一种常见并发症，炎症可能导致患者黄斑部位水肿，如不及时治疗，可能会导致视力模糊、视力丧失并最终失明。 8、科伦博泰生物：KL130008胶囊作用机制：JAK1/2抑制剂适应症：重度斑秃 KL130008胶囊为科伦药业控股子公司科伦博泰生物开发的靶向JAK1和JAK2激酶的选择性抑制剂。公开资料显示，由JAK介导的信号通路包括JAK-STAT通路等，而参与斑秃发病机制的许多细胞因子都依赖于JAK-STAT信号传导，如IL-2、IL-7、IL-15、IL-21和IFN-γ，因此JAK-STAT被认为是斑秃治疗中有临床潜力的一个信号通路。根据科伦药业公告，KL130008已经在中国开展4项临床试验，针对类风湿关节炎适应症。本次该药新增适应症获批临床，拟用于重度斑秃患者的治疗。 9、康复得生物：重组草酸脱羧酶散适应症：继发性高草酸尿症继发性高草酸尿症是一种获得性草酸代谢紊乱疾病，特征为尿草酸排泄量增加（>540 mg/天），临床结果表现为复发性泌尿结石、肾钙质沉积症、草酸性肾损伤进而发展为慢性肾病以及终末期肾病等。根据康复得生物新闻稿介绍，重组草酸脱羧酶散（TRA16）为其自主研发的1类生物新药。它能有效在人的胃肠中降解食源性草酸，阻止草酸被胃肠道吸收过多，降低尿草酸含量。该药还有潜力治疗其他适应症，如泌尿系结石、高草酸血症、慢性肾病、多囊肾等。本次，该药在中国获批开展用于治疗继发性高草酸尿症适应症的1期和2期临床试验。 10、辉启生物：LIT-00505胶囊适应症：银屑病辉启生物自主研发的LIT-00505是一款口服小分子抑制剂，临床拟用于自身免疫性疾病。早先，该药已经于今年3月在美国获批临床。根据辉启生物新闻稿介绍，该公司成立于2018年6月，聚焦先天淋巴细胞免疫，开发新一代免疫疗法，拥有小分子药物发现技术及创新的蛋白降解剂高通量筛选技术。该公司目前已建立了以精准疾病机制引导的创新药物研发平台，研发产品管线正在快速推进。除了上述新药，本周还有多款1类新药获得临床试验默示许可，如三生国健引进的抗P-选凝素糖蛋白配基-1（PSGL-1）抗体SSGJ-617注射液、NewAmsterdam Pharma公司在研口服选择性胆固醇酯转移蛋白（CETP）抑制剂obicetrapib片等等，本文不再一一介绍。希望这些1类新药后续临床研究顺利进行，早日为患者造福。参考资料： [1]中国国家药监局药品审评中心（CDE）官网.Retrieved Mar 25，2022, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]各公司官网及公开资料内容来源于网络，如有侵权，请联系删除，谢谢

免疫疗法创新药小分子药物抗体AACR会议