MARK3

更新于：2025-05-07

基本信息

别名

C-TAK1、Cdc25C-associated protein kinase 1、CTAK1

+ [11]

简介

Serine/threonine-protein kinase (PubMed:16822840, PubMed:16980613, PubMed:23666762). Involved in the specific phosphorylation of microtubule-associated proteins for MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU (PubMed:23666762). Phosphorylates CDC25C on 'Ser-216' (PubMed:12941695). Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus (PubMed:16980613). Regulates localization and activity of MITF by mediating its phosphorylation, promoting subsequent interaction between MITF and 14-3-3 and retention in the cytosol (PubMed:16822840). Negatively regulates the Hippo signaling pathway and antagonizes the phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase activity of STK3/MST2 toward LATS1 (PubMed:28087714). Phosphorylates PKP2 and KSR1 (PubMed:12941695).

关联

100 项与 MARK3 相关的临床结果

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100 项与 MARK3 相关的转化医学

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0 项与 MARK3 相关的专利（医药）

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169

项与 MARK3 相关的文献（医药）

2025-06-01·Biochemistry and Biophysics Reports

Clinical data investigation identifies MARK3 as an oncogenic driver in castration-resistant prostate cancer

Article

作者: Mishra, Parul ; Raut, Rajnikant ; Chakraborty, Amit Kumar ; Srivastava, Devesh ; Misra, Ashish ; Gupta, Parth ; Choudhury, Chumki ; Saini, Taruna ; Nayak, Vinayak ; Bais, Manish V

Castration-resistant prostate cancer (CRPC) represents an aggressive and fatal form of prostate cancer that emerges following resistance to androgen deprivation therapy. Despite the availability of various drugs that can enhance the quality and prolong the survival of CRPC patients, resistance to these therapies is frequently observed, making the disease increasingly difficult to treat. Altered expression of kinases and phosphatases is a critical driver of CRPC and presents a potential target for more effective treatments. In this study, we have performed comprehensive transcriptomic analysis of ∼359 normal and CRPC patient samples from The Cancer Genome Atlas to identify the differentially expressed kinases and phosphatases in patient samples. We shortlisted the candidate genes based on their differential expression profiles, associations with patient survival, Gleason scores, and their impact on the fitness of prostate cancer cell lines. Our in-silico analysis identified microtubule affinity-regulating kinase 3 (MARK3) as a novel CRPC driver that is upregulated in CRPC patients, linked with poor survival outcomes, and affects the fitness of CRPC cells. Furthermore, we found that pharmacological inhibition of MARK3 using PCC0208017, a MARK3 inhibitor, leads to reduced cell viability, migration potential, and cell cycle arrest in the G1 phase in prostate cancer cells. Additionally, RNA sequencing analysis in 22Rv1 cells treated with the MARK3 inhibitor revealed that MARK3 influences genes involved in androgen response, epithelial-mesenchymal transition, mTOR, and myc-signalling, underscoring its pivotal role in CRPC progression. Taken together, our results establish MARK3 as a novel and promising therapeutic target in CRPC.

2025-03-13·ACS Medicinal Chemistry Letters

In-Silico Screening-Based Discovery of New Natural eEF2K Inhibitors with Neuritogenic Activity

Article

作者: Wang, Ying ; Chen, Xiao-Xia ; Hu, Li-Jun ; Zhang, Xiao-Qi ; Shi, Lei ; Wang, Xinyu ; Zhang, Shiqing ; Huang, Xiao-Jun ; Ye, Wen-Cai ; Guo, Lingling ; Wang, Shu-Qin

Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.

2025-01-01·European Journal of Medicinal Chemistry

Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold

Article

作者: Elgaher, Walid A M ; Cochet, Claude ; Engel, Matthias ; Abadi, Ashraf H. ; Hamed, Mostafa M ; ElHady, Ahmed K ; Liu, Ting ; Khalifa, Hend ; Hamed, Mostafa M. ; Abadi, Ashraf H ; Filhol-Cochet, Odile ; Filhol, Odile ; ElHady, Ahmed K. ; Elgaher, Walid A.M. ; Abdel-Halim, Mohammad

CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC₅₀ values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC₅₀ value of 36.7 nM and a notable cellular activity with a GI₅₀ of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range.

项与 MARK3 相关的新闻（医药）

2023-12-22

·生物谷

Clin Epigenet：慢性偏头痛研究或能揭示降低机体偏头痛频率的特殊遗传学机制

来自昆士兰理工大学等机构的科学家们通过研究揭示了慢性偏头痛患者在逐渐停用偏头痛药物后机体偏头痛频率降低背后的生物学机制。慢性偏头痛是一种高度致残的亚型偏头痛，其影响着近2%的普通人群，理解偏头痛的慢性化对于开发更好的疗法和预防性策略至关重要，偏头痛慢性化的一种重要因素就是急性头痛药物的过度使用，然而，发作性偏头痛转化为慢性偏头痛背后的分子机制，目前研究人员尚未阐明。近日，一篇发表在国际杂志Clinical Epigenetics上题为“Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study”的研究报告中，来自昆士兰理工大学等机构的科学家们通过研究揭示了慢性偏头痛患者在逐渐停用偏头痛药物后机体偏头痛频率降低背后的生物学机制。文章中，研究人员揭示了他们如何发现从发作性偏头痛到慢性偏头痛转变过程中所涉及的两个基因的表观遗传学改变。研究者表示，慢性偏头痛是大约2%的普通人群所面临的主要头痛问题；研究者Divya Mehta说道，过度使用缓解急性头痛和其它药物是慢性偏头痛发生发展和维持的一个重要因素。如果患者每月15天或更多的时间会头痛，且会持续3个月或更长时间，其中有8天符合偏头痛的标准，那么研究人员就将这种偏头痛归类为慢性偏头痛，因此这或许是一种高度致残的偏头痛类型。如今研究人员开始理解偏头痛慢性化的过程（即某些偏头痛患者的疾病发作越来越频繁），以及如何逆转这一过程。研究人员调查了DNA甲基化的纵向改变，DNA甲基化是一种表观遗传学修饰，是为了对包括治疗性药物在内的环境因素产生反应而将在DNA分子上添加化学标签，从而就能实现基因的开启或关闭。慢性偏头痛研究或能揭示降低机体偏头痛频率的特殊遗传学机制。图片来源：Clinical Epigenetics (2023). DOI:10.1186/s13148-023-01604-8 文章中，研究人员对慢性偏头痛患者在药物疗法治疗开始时和停药12周后机体的血液进行采集并分析，Sutherland博士说道，我们让患者记录其头痛日志，并将每月的头痛和偏头痛天数减少50%以上的患者（应答者）与无应答者进行比较，从而识别出与其对疗法产生反应相关的DNA甲基化改变。在所有患者中，59.8%的患者在12周的停药期结束时又复发成为发作性偏头痛患者。而且研究人员发现，HDAC4基因的表观遗传学改变与急性药物停药后头痛天数的平均减少有关，DNA甲基化水平的降低与头痛天数的减少有一定关联。其次，研究者发现，MARK3基因内的DNA甲基化与偏头痛天数的平均减少有关；MARK3基因在基线时的DNA甲基化水平较低或与每月偏头痛天数减少有关，且其被发现是一种预测患者对疗法产生反应的特殊生物标志物。这些研究发现具有重大的临床意义，因为其能揭示这些基因或许能作为偏头痛的新型治疗性靶点。综上，本文研究结果表明，与疗法反应相关的HDAC4的DNA甲基化水平的纵向降低，以及基线MARK3的DNA甲基化或能作为指示偏头痛患者对疗法产生反应的早期生物标志物，从而就为揭示染色质结构和突触可塑性相关通路在偏头痛慢性化中的重要作用提供了一定的支持，并引入了HDAC4和MARK3作为新型的治疗性靶点。（生物谷Bioon.com）原始出处： Mehta, D., de Boer, I., Sutherland, H.G. et al. Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study. Clin Epigenet 15, 190 (2023). doi：10.1186/s13148-023-01604-8

临床结果临床研究