更新于：2024-09-19

MINK1

更新于：2024-09-19

基本信息

别名

B55、GCK family kinase MiNK、MAP4K6

+ [12]

简介

Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1. Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration.

关联

100 项与 MINK1 相关的临床结果

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100 项与 MINK1 相关的转化医学

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0 项与 MINK1 相关的专利（医药）

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231

项与 MINK1 相关的文献（医药）

2024-08-01·Journal of Pharmacology and Experimental Therapeutics

Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases

Review

作者: Ampadu, Felix ; Awasthi, Vibhudutta ; Joshi, Aditya D

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review provides an overview of our current knowledge of MAP4K4 structure and expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling pathways and, in the future, will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. SIGNIFICANCE STATEMENT: Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 biology within the context of metabolic dysfunction and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver and metabolic diseases.

2024-07-11·Journal of Medicinal Chemistry

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Plasmodium falciparum Phosphatidylinositol-4-kinase and Hemozoin Formation with In Vivo Efficacy

Article

作者: Sevilleno, Nicole ; Bhana, Ashlyn D ; Sypu, Venkata S ; Clements, Monica ; Dziwornu, Godwin Akpeko ; van der Watt, Mariette ; Pasaje, Charisse Flerida ; Fienberg, Stephen ; Mahato, Rohit ; Njoroge, Mathew ; Coyle, Rachael ; Niles, Jacquin C ; Coulson, Lauren B ; Seanego, Donald ; Chakraborty, Arnish ; Chibale, Kelly ; Ferreira, Jasmin ; Garnie, Larnelle F ; Lee, Marcus C S ; de Bruijni, Marloes H C ; Birkholtz, Lyn-Marié ; Godoy, Luiz C ; Korkor, Constance M ; Basarab, Gregory S ; Reader, Janette ; Salomane, Nicolaas ; Wicht, Kathryn J ; Samanta, Sauvik ; Bolscher, Judith M ; Wittlin, Sergio ; Taylor, Dale ; Teixeira, Nicole ; Gibhard, Liezl ; Olckers, Ronald ; Ghorpade, Sandeep R

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.

2024-07-01·Cell Reports

PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis

Article

作者: Salvador-Barberó, Beatriz ; Ortega, Sagrario ; Aguirre-Portolés, Cristina ; Álvarez-Fernández, Mónica ; Ruiz-Torres, Miguel ; Villarroya-Beltri, Carolina ; Sanz-Flores, María ; Megías, Diego ; El Bakkali, Aicha ; Malumbres, Marcos ; Gerlich, Daniel W

Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

项与 MINK1 相关的新闻（医药）

2022-06-21

·生物制品圈

免疫治疗新星：靶向HPK1的药物研发进展

造血祖细胞激酶1（Hematopoietic progenitor kinase 1 ，HPK1）是T细胞受体、B细胞受体和树突状细胞的负调节因子。HPK1激酶功能的丧失增加了细胞因子的分泌，增强了T细胞信号传导、病毒清除和肿瘤生长抑制。因此，HPK1被认为是肿瘤免疫治疗的一个有希望的靶点。据报道，几种HPK1抑制剂可调节T细胞功能。此外，还开发了能够诱导HPK1降解的HPK1靶向蛋白。最新一期JMC上，尤启冬等综述了HPK1的蛋白结构、功能和抑制剂的研究现状，并对HPK1靶向药物的未来发展提出了展望。HPK1是hematopoietic progenitor kinase 1（造血祖细胞激酶1）的简称，又名MAP4K1，是MAP4K家族的成员之一，它是一种丝/苏氨酸蛋白激酶。MAP4K家族中除HPK1外还有5个成员，包括MAP3K2、MAP4K3、MAP4K4、MAP4K5和MAP4K6。HPK1蛋白结构由N端激酶结构域（HPK1-KD）、四个富含脯氨酸（PR）的基序（PR1、PR2、PR3、PR4）和C端的柠檬酸同源结构域组成。PR1、PR2和PR4含有典型的II类结合基序，可与一系列含有Src同源3（SH3）结构域的衔接蛋白结合，如Grb2、Gads、Crk I/II、CrkL、Nck和HIP-55。这种结合模式不诱导磷酸化，表明HPK1蛋白的支架作用。HPK1的C端同源结构域可能作为调节结构域参与分子间相互作用。全长HPK1可在半胱氨酸蛋白酶切割位点（DDVD）被Caspas3切割，从而提高HPK1-KD的催化活性。HPK1激酶HPK1可与许多接头蛋白结合，如SLP76家族，Gads、HIP-55、GRB2家族，LAT、CRK家族等相互作用，活化造血干细胞的SAPK/JNK信号途径，从而对TCR通路进行负向调节。HPK1激酶是TCR信号的关键负反馈调节因子，能负调控树突细胞活化和T细胞与B细胞反馈；而抑制HPK1可增强T细胞活性，从而提高抗肿瘤免疫。HPK1主要由造血细胞包括其祖细胞表达。在T-细胞中，HPK1通过磷酰化SLP76上的Ser376和Gads上的Thr254激活SLP76，其磷酸化的复合体参与ERK信号途径的下调，并接到SLP-76的泛素化降解过程，导致TCR信号通路和T细胞增殖下降。2018年，Genentech的研究人员在Cell report上发表了一篇论文，显示共同阻断HPK1和PD-L1增强了抗肿瘤反应，证实HPK1可能提高检查点抑制剂功效。2020年8月28日，清华大学药学院廖学斌课题组与中山大学魏来课题组合作在《Cancer Cell》杂志上发表文章“造血祖细胞激酶1 (HPK1)通过有效调控T细胞功能，成为T细胞免疫治疗的药物靶点（Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies）”，该工作进一步证实HPK1可成为T细胞免疫疗法的药物热门研发靶点。HPK1抑制剂十多年前，研发人员就发现了HPK1可能是一种潜在的癌症免疫治疗靶点，但截止目前尚还没有相关药物上市。HPK1抑制剂开发所面临的挑战主要是HPK1 家族成员功能不同，设计高选择性抑制性化合物难度较大。据不完全统计，处于临床研发阶段的HPK1抑制剂包括：CFI-402411：是Treadwell Therapeutics公司研发的一种口服强效HPK1激酶抑制剂。临床前研究表明CFI-402411有望作为一种潜在的单一疗法，并与多种实体和血液癌症模型中的现有检查点抑制剂结合使用。2020年9月2日，该公司宣布CFI-402411的1/2期研究将进行首次患者给药，以评估TWT-101在实体瘤患者中作为单一疗法或与PD-1抑制剂联用的疗效。BGB-15025：是百济神州开发的一款高强度、高选择性的HPK1小分子口服抑制剂。2021年3月10日，百济神州公司宣布，一项针对其在研造血干细胞激酶1（HPK1）抑制剂BGB-15025的1期临床试验已完成首例患者给药。PRJ1-3024：是珠海宇繁研发的HPK1小分子抑制剂。PRJ1-3024胶囊分别于2021年11月和2022年2月在美国和中国进入临床试验阶段，主要用于胰腺癌、结直肠癌、肝癌等恶性肿瘤的免疫治疗。NDI-101150：无公开信息。其他研发中的小分子抑制剂结构包括下图（全部结构请阅读原文）等：已经报道的HPK1降解剂包括：在过去的5年中，已经报道了大量针对HPK1的小分子激酶抑制剂，大多数是ATP竞争性抑制剂。综合结构信息，作者发现与铰链相连的常见支架结构多为吲哚唑、氨基吡啶、氮杂吲哚等；面对P环的基团通常基于取代苯基或吡啶环；溶剂区域倾向于引入增溶基团如哌嗪或含氮杂环等。开发HPK1抑制剂的主要挑战是难以在MAP4K激酶家族中获得足够的选择性。此外，很难避免抑制参与TCR信号传导的其他相关激酶，如Src和其他Ste20样激酶家族。此外。已经报道了几种基于PROTAC技术的HPK1降解剂，这为靶向HPK1治疗创造了一个新的窗口，并可能进一步增强激酶的选择性。识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法小分子药物细胞疗法抗体蛋白降解靶向嵌合体