更新于：2024-05-01

HIPK2

homeodomain interacting protein kinase 2

更新于：2024-05-01

基本信息

别名

hHIPk2、HIPK2、homeodomain interacting protein kinase 2

+ [1]

简介

Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1, ZBTB4 and DAZAP2. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. In response to DNA damage, phosphorylates DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal degradation (PubMed:33591310). Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.

关联

项与 HIPK2 相关的药物

RLA-23174

靶点-

作用机制

HIPK2 inhibitors

在研机构

上海璎黎药业有限公司

原研机构

上海璎黎药业有限公司

在研适应症

肾纤维化

非在研适应症-

最高研发阶段临床申请批准

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HIPK2 相关的临床结果

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100 项与 HIPK2 相关的转化医学

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0 项与 HIPK2 相关的专利（医药）

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495

项与 HIPK2 相关的文献（医药）

2024-02-08·Human genomics

Gene expression analysis reveals diabetes-related gene signatures.

Article

作者: M I Farrim ; A Gomes ; D Milenkovic ; R Menezes

BACKGROUND:

Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction.

METHODS:

A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network.

RESULTS:

Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets.

CONCLUSIONS:

This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.

2024-01-09·ACS omega

Circular RNA HIPK2 Promotes A1 Astrocyte Activation after Spinal Cord Injury through Autophagy and Endoplasmic Reticulum Stress by Modulating miR-124-3p-Mediated Smad2 Repression

Article

作者: Yang, Jin ; Dong, Junjie ; Li, Haotian ; Gong, Zhiqiang ; Wang, Bing ; Du, Kaili ; Zhang, Chunqiang ; Bi, Hangchuan ; Wang, Junfei ; Tian, Xinpeng ; Chen, Lingqiang

Glial scarring formed by reactive astrocytes after spinal cord injury (SCI) is the primary obstacle to neuronal regeneration within the central nervous system, making them a promising target for SCI treatment. Our previous studies have demonstrated the positive impact of miR-124-3p on neuronal repair, but it remains unclear how miR-124-3p is involved in autophagy or ER stress in astrocyte activation. To answer this question, the expression of A1 astrocyte-related markers at the transcriptional and protein levels after SCI was checked in RNA-sequencing data and verified using quantitative polymerase chain reaction (qPCR) and Western blotting in vitro and in vivo. The potential interactions among circHIPK2, miR-124-3p, and Smad2 were analyzed and confirmed by bioinformatics analyses and a luciferase reporter assay. In the end, the role of miR-124-3p in autophagy, ER stress, and SCI was investigated by using Western blotting to measure key biomarkers (C3, LC3, and Chop) in the absence or presence of corresponding selective inhibitors (siRNA, 4-PBA, TG). As a result, SCI caused the increase of A1 astrocyte markers, in which the upregulated circHIPK2 directly targeted miR-124-3p, and the direct downregulating effect of Smad2 by miR-124-3p was abolished, while Agomir-124 treatment reversed this effect. Injury caused a significant change of markers for ER stress and autophagy through the circHIPK2/miR-124-3p/Smad2 pathway, which might activate the A1 phenotype, and ER stress might promote autophagy in astrocytes. In conclusion, circHIPK2 may play a functional role in sequestering miR-124-3p and facilitating the activation of A1 astrocytes through regulating Smad2-mediated downstream autophagy and ER stress pathways, providing a new perspective on potential targets for functional recovery after SCI.

2024-01-07·Journal of cellular and molecular medicine

miR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition.

Article

作者: Zhiming Shan ; Zhenchao Zhuang ; Peiyao Ren ; Li Zhao ; Danna Zheng ; Wei Chen ; Juan Jin

We previously found that miR-664a-5p is specifically expressed in urinary exosomes of idiopathic membranous nephropathy (IMN) patients. Homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, plays an important role in nephropathy. But the function of these factors and their connection in MN are unclear. To investigate the function and mechanism of miR-664a-5p in MN, the miR-664a-5p expression in HK-2 cells, exosomes, podocytes and renal tissues were studied, as well as cell growth and apoptosis of these cells, the binding of miR-664a-5p to HIPK2 mRNA, the levels of relative proteins and autophagy. The MN progression in MN mice model was also studied. Albumin increased the miR-664a-5p content and apoptosis of HK-2 cells, which was blocked by miR-664a-5p antagomir. miR-664a-5p bound to the 3' UTR of HIPK2 mRNA, resulting in the up-regulation of Calpain1, GSα shear and the inhibition of autophagy level. Autophagy inhibitor CQ blocked the protective effect of miR-664a-5p antagomir, HIPK2 overexpression, Calpain inhibitor SJA6017 on albumin-mediated injury. MiR-664a-5p from albumin-treated HK-2 cells could be horizontally transported to podocytes through exosomes. Exosomes from albumin-treated HK-2 cells promoted progression of MN mice, AAV-Anti-miR-664-5p (mouse homology miRNA) could improve them. Albumin increases the miR-664a-5p level and causes changes of HIPK2/Calpain1/GSα pathway, which leads to autophagy inhibition and apoptosis up-regulation of renal tubular epithelial cells. miR-664a-5p can horizontally enter podocytes through exosomes resulting in podocytes injury. Targeted inhibition of miR-664a-5p can reduce the apoptosis of renal tubule cells and podocytes, and may improve the MN progression.

项与 HIPK2 相关的新闻（医药）

2024-03-24

·药研发

【药研发0325】锐康迪微球优先审评 | 璎黎肾纤维化新药获批IND...

「本文共：15条资讯，阅读时长约：3分钟」今日头条锐康迪微球优先审评。Recordati集团旗下锐康迪医药「注射用双羟萘酸帕瑞肽微球」获CDE拟纳入优先审评，用于治疗无法手术或手术后未治愈和通过另一种生长抑素类似物治疗控制不佳的成人肢端肥大症患者。这是一款长效帕瑞肽产品（pasireotide pamoate），为第二代生长抑素类似物（SRL）。此前博鳌乐城维健罕见病临床医学中心已引进该产品应用于肢端肥大症患者的临床治疗。国内药讯1.益普生罕见病新药报产。Albireo公司与益普生开发的回肠胆汁酸转运蛋白（IBAT）抑制剂odevixibat胶囊（Bylvay）的上市申请获CDE受理。Odevixibat可阻断肠胆汁酸经过肠肝循环回流入肝，从而减轻肝脏内及循环内的胆汁酸浓度。去年11月，CDE已将该新药纳入优先审评，拟用于治疗6个月或以上患者的进行性家族性肝内胆汁淤积症（PFIC）。2.康方双抗亮相ELCC2024。康方生物与Summit公司联合开发的PD-1/VEG双抗ivonescimab在ELCC 2024年会上公布了治疗晚期或转移性非小细胞肺癌（NSCLC）的Ⅱ期临床AK112-201积极结果。数据显示，ivonescimab联合化疗在鳞状和非鳞状NSCLC患者中的中位PFS分别达到11.1个月（95% CI：9.5–16.3个月）和13.3个月（95% CI：8.3–16.4个月）。在中位随访时间为22.1个月后，两个患者亚组的中位总生存期均尚未达到。3.璎黎肾纤维化新药获批IND。璎黎药业1类化药RLA-23174片获国家药监局临床许可，拟开发用于治疗肾纤维化。RLA-23174是一款HIPK2变构抑制剂，通过影响HIPK2和Smad3之间的相互作用而不抑制HIPK2的激酶活性，从而仅抑制TGF-β/Smad3信号通路且不影响Smad2和p53的磷酸化。在临床前研究中，RLA-23174已显示出积极的抗纤维化效果和良好的安全性。4.石药又一款ADC获批临床。石药集团旗下巨石生物1类生物制品SYS6023获国家药监局临床许可，拟开发治疗晚期实体瘤患者。SYS6023是一款抗体偶联药物（ADC），可与肿瘤表面的特异性受体结合，通过内吞作用进入细胞并释放毒素，达到杀伤肿瘤细胞的作用。在临床前研究中，该产品对多种癌症均显示有较好的抗肿瘤作用。石药集团在ADC产品方面的靶点目前已涵盖了HER2、Nectin-4、Claudin 18.2、EGFR等。5.健康元引入COPD小分子新药。健康元与拜耳达成合作许可协议，获得后者一款小分子脯氨酰内肽酶（PREP）抑制剂在国内开发、商业化和生产的独家许可，应用于慢性阻塞性肺疾病（COPD）的治疗。该新药通过抑制PREP活性，有效阻止了COPD炎症介质的产生，有望为COPD患者提供新的治疗选择。该新药目前已在欧洲完成I期临床试验。国际药讯1.艾伯维卵巢癌ADC获批上市。艾伯维FRα靶向ADC新药Elahere（mirvetuximab soravtansine）获FDA由加速批准转换为完全批准，用于治疗叶酸受体α（FRα）阳性、铂类耐药的上皮性卵巢癌、输卵管癌或原发性腹膜癌患者。在Ⅲ期临床MIRASOL中，与化疗相比，Elahere联合治疗显著提高了患者总生存期（中位OS：16.46个月和12.75个月，p=0.0046），使死亡风险降低33%。2023年11月，艾伯维通过收购ImmunoGen公司获得该产品，华东医药拥有该药的大中华区权益。2.强生PAH组合疗法获批上市。强生单片剂组合疗法Opsynvi（M/T STCT，（马昔腾坦/他达拉非））获FDA批准上市，成为首款单片剂组合疗法，用于长期治疗WHO功能分级（FC）为II-III级的肺动脉高压（PAH）成人患者。在Ⅲ期A DUE临床中，与马昔腾坦或他达拉非单药治疗相比，M/T STCT治疗第16周显着降低了患者肺血管阻力（PVR），降幅达到39%（vs18%，p<0.0001）。3.诺华FIC新药获CHMP推荐上市。诺华补体B因子抑制剂Fabhalta（iptacopan）获欧盟人用药品委员会（CHMP）推荐批准，用于治疗患有溶血性贫血的成人阵发性睡眠性血红蛋白尿症（PNH）患者。在Ⅲ期临床APPLY-PNH中，在24周不需要输血的情况下，iptacopan治疗实现血红蛋白水平较基线增加2g/dL的患者比例达到82.3%；避免输血率达到94.8%。去年年底，该新药已获FDA批准上市，是首款PNH口服单药疗法。4.诺和诺德超长效胰岛素获CHMP支持上市。欧洲药品管理局人用药品委员会（CHMP）推荐批准诺和诺德每周1次超长效胰岛素icodec（Awiqli）上市，用于治疗成人糖尿病。在Ⅲa期临床ONWARDS中，与每日一次甘精胰岛素U100相比，每周一次icodec治疗具有非劣效性（P<0.001）和优效性（P=0.02），两组患者Hb1Ac水平的平均降幅分别为1.55%和1.35%，估计的组间差异为-0.19%，95% CI：-0.36~-0.03。目前，该新药也正接受FDA和CDE的上市监管审查。5.干眼症创新眼药水Ⅱ期临床积极。OKYO Pharma脂质偶联chemerin肽激动剂眼药水OK-101（0.05%）治疗干眼症（DED）的Ⅱ期临床结果积极。OK-101通过靶向G蛋白偶联受体ChemR23以启动眼部免疫细胞的抗炎症反应。数据显示，第15天时，OK-101治疗显著缓解了患者的眼痛症状，也显著改善了泪膜破裂时间；而且OK-101具有良好的滴眼舒适度，没有出现与药物相关的严重不良事件。6.卫材老年痴呆新药上市延期。卫材Aβ抗体lecanemab（仑卡奈单抗）上市申请被欧洲EMA推迟审批。EMA已取消在3月11日召开的神经科学咨询小组（SAG-N）会议上获得的关于lecanemab的积极建议，重新召开SAG-N会议再次审议lecanemab，以确保专家与该产品没有利益冲突。去年7月，FDA已批准lecanemab的加速上市许可转变为完成批准，用于治疗轻度阿尔茨海默症（AD）及相关轻度认知障碍（MCI）疾病。医药热点1.全球最贵药物易主。近日，Orchard公司对外公开其刚刚获批的早发性异染性脑白质营养不良（MLD）一次性基因疗法Lenmeldy在美国一次性治疗的批发采购成本（WAC）为425万美元（约合人民币3066万元）。而去年9月，外媒Fierce Pharma发布了2023年美国最昂贵药物排名TOP10，其中基因疗法占据半壁江山，最贵的为首款B型血友病基因疗法——UniQure公司的Hemgenix，定价350万美元。这也意味着Lenmeldy已登上最贵药物榜首。2.国家明文规定预制菜不添加防腐剂。3月21日，国家市场监管总局等六部门联合印发《关于加强预制菜食品安全监管促进产业高质量发展的通知》，明确规定预制菜中不添加防腐剂，规范预制菜范围，旨在强化预制菜食品安全监管。国家市场监督管理总局相关负责人回应，预制菜也称预制菜肴，预制菜虽经过工业化预制，但仍属于菜肴范畴，消费者在菜肴烹制过程中一般不添加防腐剂，规定预制菜中不添加防腐剂更加符合消费者期待。3.CDMO巨头「龙沙」拿下罗氏工厂。3月20日，全球CDMO巨头企业龙沙（Lonza）宣布，将以总交易金额额12亿美元收购罗氏位于美国瓦卡维尔（Vacaville）的大规模生物制药工厂。该厂是全球产量最大的生物制剂生产基地之一，生物反应器总容量约为33万升。龙沙计划投资约5亿瑞士法郎（约5.623亿美元），用于升级该设施并增强该基地的能力，以适应下一代哺乳动物生物药疗法。根据协议，该工厂的约750名员工将由龙沙提供就业机会，该工厂目前生产的产品也将继续由龙沙提供。评审动态 1. CDE新药受理情况（03月24日) 2. FDA新药获批情况（北美03月22日）股市资讯上个交易日 A 股医药板块 -1.18%涨幅前三跌幅前三万泽股份+10.04% 大理药业-10.02%永顺生物 +5.46% 龙津药业 -6.50%江苏吴中 +5.40% 粤万年青 -5.47%[舒泰神]公司收到关于多中心、随机、双盲、安慰剂平行对照I/11期探索BDB-001注射液治疗中重度化脓性汗腺炎患者的安全性和有效性的临床研究报告。取得III期临床研究总结报告。[贝达药业]产品BPI-221351片药物临床试验申请获得NMPA批准。[海思科]创新药HSK39297片新适应症拟用于治疗溶血性疾病获得药物临床试验批准通知书。[亿帆医药]控股子公司在研产品艾贝格司亭 a注射液(Ryzneuta®)获欧盟委员会批准上市。- The End -戳“阅读原文”，了解更多医药研发及股市资讯。

优先审批临床申请临床2期抗体药物偶联物申请上市

2024-03-23

·医药观澜

璎黎药业联合开发，创新HIPK2抑制剂在中国获批临床！

▎药明康德内容团队编辑3月22日，璎黎药业宣布其已收到中国国家药品监督管理局核准签发的《药物临床试验批准通知书》，批准该公司开展新型小分子HIPK2变构抑制剂RLA-23174片治疗肾纤维化的临床试验。HIPK是定位于细胞核内的丝氨酸/苏氨酸蛋白激酶，表达于多种组织中，包括大脑、肺、肝、肾、皮肤、肌肉等。HIPK家族有四个直系同源物，称为HIPK1、HIPK2、HIPK3、HIPK4。在HIPK家族中，HIPK2与纤维化关系密切，如心肌结构重建、肝脏纤维化、肺纤维化，肾脏纤维化等，是研究抗纤维化治疗的重要靶点。RLA-23174是璎黎药业和Rila Therapeutics公司合作开发的一种新型小分子HIPK2变构抑制剂。该候选药可通过影响HIPK2和Smad3之间的相互作用来抑制TGF-β/Smad3信号通路，不抑制HIPK2的激酶活性，从而不影响Smad2和p53的磷酸化。由此RLA-23174在发挥抗纤维化作用的同时，还能减少因抑制HIPK2而产生的多种不良反应。临床前研究表明，RLA-23174具有良好的抗纤维化效果、很高的体内外活性、优良的动物体内药代特性和良好的安全性。璎黎药业研发总裁兼上海璎黎总经理许祖盛博士表示：“目前对HIPK2影响肾纤维化的发病机制的认识已取得重要进展，但还没有相应发病机制的新药进入临床研究阶段，临床上非常缺乏针对肾纤维化的有效治疗药物。此次RLA-23174获批临床进入临床研究后，公司将积极推进其临床试验的开展，尽早地为肾纤维化病人提供治疗选择。”参考资料：[1]璎黎药业首个联合开发合作项目-全球新靶点HIPK2抑制剂RLA-23174获得中国临床试验许可. Retrieved Mar 22, 2024. From https://mp.weixin.qq.com/s/WIF_Ml3Y49QDcNgZQ9jVWg本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

申请上市临床1期

2024-03-22

·医药地理

璎黎药业HIPK2抑制剂RLA-23174获得中国临床试验许可

3月22日，上海璎黎药业有限公司（以下简称“璎黎药业”）收到国家药品监督管理局核准签发的《药物临床试验批准通知书》，批准公司开展RLA-23174片治疗肾纤维化的临床试验。RLA-23174是璎黎药业和Rila Therapeutics公司合作开发的一种新型小分子HIPK2变构抑制剂。RLA-23174的发明人为全球肾病领域的国际权威专家，早在2015年已经发现了HIPK2靶点对肾脏纤维化的治疗潜力，璎黎药业于2022年达成关于RLA-23174的战略合作。3月22日药品受理信息来源：Pharma ONE智能药物大数据分析平台3月22日，CDE公示了23条药品受理信息（按受理号区分），从“药品类型”上看，“化药”共有17款，“治疗用生物制品”共有1款，“治疗用生物制品”共有1款，“中药”共有3款。从“申请类型”上看，“补充申请”共有5款，“新药”共有4款，“仿制”共有8款，“进口”共有5款。从“注册分类”上看，“1类药品”共有3款，“3类药品”共有3款，“4类药品”共有5款，“5.1类药品”共有4款。END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

申请上市临床申请