更新于：2024-11-01

Aurora A

更新于：2024-11-01

基本信息

别名

serine/threonine kinase 6、AIK、AIRK1

+ [24]

简介

Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression (PubMed:26246606, PubMed:12390251, PubMed:18615013, PubMed:11039908, PubMed:17125279, PubMed:17360485). Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis (PubMed:26246606, PubMed:14523000). Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (PubMed:27335426). Required for initial activation of CDK1 at centrosomes (PubMed:13678582, PubMed:15128871). Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2 (PubMed:18056443, PubMed:15128871, PubMed:14702041, PubMed:11551964, PubMed:15147269, PubMed:15987997, PubMed:17604723, PubMed:18615013). Regulates KIF2A tubulin depolymerase activity (PubMed:19351716). Important for microtubule formation and/or stabilization (PubMed:18056443). Required for normal axon formation (PubMed:19812038). Plays a role in microtubule remodeling during neurite extension (PubMed:19668197). Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53 (PubMed:14702041). Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity (PubMed:11551964). Inhibits cilia outgrowth (By similarity). Required for cilia disassembly via phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723, PubMed:20643351). Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (PubMed:28218735).

关联

项与 Aurora A 相关的药物

Tinengotinib

靶点

Aurora A x Aurora B x CSF-1R x FGFR1 x FGFR2 x FGFR3 x JAK1 x JAK2 x VEGFR

作用机制

Aurora A抑制剂 [+8]

在研机构

药捷安康（南京）科技股份有限公司初创企业

原研机构

药捷安康（南京）科技股份有限公司初创企业

在研适应症

胆管癌 [+11]

非在研适应症-

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

ENMD-2076

靶点

Aurora A x CSF-1R x FGFRs x FLT3 x VEGFR x c-Kit

作用机制

Aurora A抑制剂 [+5]

在研机构

Alcami Carolinas Corp. [+1]

原研机构

CASI Pharmaceuticals, Inc.

在研适应症

三阴性乳腺癌

非在研适应症

晚期癌症 [+9]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Alisertib

靶点

Aurora A

作用机制

Aurora A抑制剂

在研机构

Puma Biotechnology, Inc. [+3]

原研机构

Takeda Pharmaceutical Co., Ltd.

在研适应症

复发性乳腺癌 [+7]

非在研适应症

腺泡细胞癌 [+60]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

141

项与 Aurora A 相关的临床试验

NCT06369285 / Recruiting临床2期

A Phase 2 Study of Alisertib in Combination with Endocrine Therapy in Patients with HR+, HER2-negative Recurrent or Metastatic Breast Cancer

PUMA-ALI-1201 is a randomized, dose optimization, multicenter, Phase 2 study of alisertib administered in combination with endocrine therapy in participants with pathology-confirmed HR-positive/HER2-negative metastatic breast cancer (MBC) following progression on or after at least two prior lines of endocrine therapy in the recurrent or metastatic setting. This study is intended to evaluate the optimal alisertib dose administered in combination with the selected endocrine therapy. The study is also planned to evaluate the efficacy, safety, and pharmacokinetics of alisertib in combination with endocrine and to identify the biomarker-defined subgroup(s) that may benefit most from combined alisertib and endocrine therapy.

开始日期2024-12-31

申办/合作机构

Puma Biotechnology, Inc.

NCT06519721 / RecruitingN/AIIT

Safety and Efficacy Study of Lenvatinib Combined With VIC-1911 for the Treatment of Advanced Hepatocellular Carcinoma

This study is a single-arm, open-label trial to clarify the safety and efficacy of the combined treatment of lenvatinib and VIC-1911 in patients with advanced liver cancer.

开始日期2024-08-01

申办/合作机构-

NCT06457919 / Recruiting临床1/2期IIT

A Phase 1b/2 Study Evaluating the Activity of Tinengotinib (TT-00420) in Combination With Androgen Receptor Signaling Inhibitors (ARSIs) in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

The purpose of this study is to find out whether tinengotinib in combination with abiraterone acetate and prednisone or enzalutamide is a safe treatment that causes few or mild side effects in people with metastatic castration-resistant prostate cancer (mCRPC).

开始日期2024-06-04

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

100 项与 Aurora A 相关的临床结果

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100 项与 Aurora A 相关的转化医学

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0 项与 Aurora A 相关的专利（医药）

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3,802

项与 Aurora A 相关的文献（医药）

2025-03-01·Biomaterials

Helicobacter pylori VacA-induced mitochondrial damage in the gastric pit cells of the antrum and therapeutic rescue

Article

作者: Bae, Jae-Sung ; Han, Man-Hoon ; Cho, Hyun-Soo ; Son, Myung Jin ; Jang, Ah-Ra ; Mun, Seon Ju ; Jeong, Yu-Jin ; Kwon, Yong Hwan ; Ryu, Choong-Min ; Park, Jong-Hwan ; Son, Mi-Young ; Lee, Moo-Seung ; Kwon, Ohman ; Son, Ye Seul ; Jung, Cho-Rok ; Park, Doo-Sang ; Bae, Jae-sung ; Park, Ji Hye ; Hur, Keun ; Jeon, Sojeong

Exploring host cell specificity, pathogenicity, and molecular mechanisms of the vacuolating cytotoxin A (VacA), secreted by Helicobacter pylori (Hp) is crucial for developing novel treatment strategies. VacA affects subcellular events, particularly mitochondria, at a cell-type-specific level. However, the lack of reliable models that mimic VacA-induced subcellular damages and enable novel drug screening linked to the human stomach clinically limits our understanding of the mitochondrial networks in vivo. Here, human antrum gastric organoids (hAGOs) and tissue samples from Hp-infected patients were used to show the toxic effects of VacA-induced mitochondrial damage mainly in mucus-producing gastric pit cells by employing transcriptional, translational, and functional analyses. In VacA-intoxicated or Hp-infected hAGOs, robust mitochondrial fragmentation in gastric pit cells reduced ATP production during respiration, and loss of mucosal barrier integrity was first demonstrated experimentally. Using hAGOs, clinically relevant small molecules were screened for efficacy, and MLN8054, an Aurora kinase A inhibitor, reversed VacA-induced mitochondrial damage and loss of gastric epithelium integrity. MLN8054 was effective in VacA-treated and Hp-infected hAGOs and mice, highlighting hAGOs as a promising drug-screening model. These findings suggest that mitochondrial quality control may serve as a promising therapeutic target for Hp VacA-mediated toxicity and disease progression.

2024-12-31·Molecular & Cellular Oncology

Molecular analysis to identify novel potential biomarkers as drug targets in colorectal cancer therapy: an integrated bioinformatics analysis

Article

作者: Jayaraman, Selvaraj ; Veeraraghavan, Vishnu Priya ; Natarajan, Sathan Raj ; Rajagopal, Ponnulakshmi ; Palanisamy, Chella Perumal ; Alsulami, Tawfiq S ; Krishnamoorthy, Rajapandiyan ; Gatasheh, Mansour K

Colorectal cancer (CRC) is a heterogeneous disease that requires new diagnostic and prognostic markers. Integrated bioinformatics approach to identify novel therapeutic targets associated with CRC. Using GEO2R identified DEGs in CRC, and Funrich software facilitated the visualization of DEGs through Venn diagrams. From a total of 114 enhanced DEGs, potential hub genes were further filtered based on their nodal strength and edges using STRING database. To gain insights into the functional roles of these hub genes, gene ontology and pathway enrichment were conducted thorough g: profiler web server. Subsequently, overall survival plots from GEPIA and oncogenic predictive functions like mRNA expressions for stages and nodal metastasis were employed to identify hub genes in CRC patient samples. Additionally, the cBioPortal and HPA databases also revealed genetic alterations and expression levels in these hub genes in CRC patients, further supporting their involvement in colorectal cancer. Gene expression by RT-PCR shows upregulation of hub genes in HT-29 cells. Finally, our integrated bioinformatic analysis revealed that ABCE1, AURKA, HSPD1, PHKA1, CDK4, and YWHAE as hub genes with potential oncogenic roles in CRC. These genes hold promise as diagnostic and prognostic markers for colorectal tumorigenesis, providing insights into targeted therapies for improved patient outcomes.

2024-12-31·Pharmaceutical Biology

Tabersonine enhances cisplatin sensitivity by modulating Aurora kinase A and suppressing epithelial–mesenchymal transition in triple-negative breast cancer

Article

作者: Liu, Yuanhong ; Yan, Yuanliang ; Yi, Qiaoli ; Chen, Xi ; Xu, Zhijie

CONTEXTTabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated.OBJECTIVEThis study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP).MATERIALS AND METHODSAfter tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes.RESULTSTabersonine demonstrated inhibitory effects on TNBC cells, with IC₅₀ values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine.DISCUSSION AND CONCLUSIONSTabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.

147

项与 Aurora A 相关的新闻（医药）

2024-10-24

·BioSpace

Puma Biotechnology to Host Conference Call to Discuss Third Quarter Financial Results

LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NASDAQ:PBYI), a biopharmaceutical company, will host a conference call at 1:30 p.m. PST/4:30 p.m. EST on Thursday, November 7, 2024, following the release of its third quarter 2024 financial results. The call may be accessed by dialing 1-877-709-8150 (domestic) or 1-201-689-8354 (international). Please dial in at least 10 minutes in advance and inform the operator that you would like to join the “Puma Biotechnology Conference Call.” A live webcast of the conference call and presentation slides may be accessed on the Investors section of the Puma Biotechnology website at . A replay of the call will be available shortly after completion of the call and will be archived on Puma’s website for 90 days. About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral), in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX® is a registered trademark of Puma Biotechnology, Inc. In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA™-Lung 1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. Further information about Puma Biotechnology may be found at . Contacts Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc., +1 424 248 6500 info@pumabiotechnology.com ir@pumabiotechnology.com David Schull or Olipriya Das, Russo Partners, +1 212 845 4200 david.schull@russopartnersllc.com olipriya.das@russopartnersllc.com

上市批准引进/卖出临床2期临床1期财报

2024-09-29

·精准药物

一类Aurora A-TPX2 PPI 抑制剂的发现

Aurora A是一种丝氨酸/苏氨酸蛋白激酶，在有丝分裂的早期阶段起重要作用；同时也是一个研究比较多的抗肿瘤靶点。目前报道有很多ATP口袋的竞争性激酶抑制剂 (如下图第一个)，但选择性可能会是挑战。 Aurora A与其它蛋白如TPX2、N-Myc互作发挥作用，因此破坏相应的PPI也是一种途径，而且可以期待选择性会好得多。但PPI抑制剂的研发一般认为挑战比较大。这里报道了一类Aurora A-TPX2的PPI抑制剂，并且展现出体内活性。其实在这之前，已经有这类小分子报道 (下图最后一个)，但也来自同一机构。这里主要看一个PPI抑制剂的案例，从筛选hit到优化为有体内药效的分子。PPI抑制剂也有难有易，但总体来说挑战比较大；这里这个例子看起来不算很挑战，但也不easy。分子hit是筛选来的，之前他们是用了HTS筛选了1万7 rationally selected compounds (focused library?)，这篇文章他们筛选了600个fragments，规模都不大。筛选离不开assay。fragment筛选他们用的是先TSA后ligand-based NMR，后面竞争性FP assay、co-crystal、ITC。最开始的fragment hit表现不出FP活性，也拿不到共晶。围绕hit做了简单修饰后，得到的fragment如分子2可以测得63μM活性，并拿到共晶。之后基于结构设计，逐步优化活性，最终得到后面做体内药效的分子CAM2602。其中一些SAR也比较有意思，感兴趣可以结合结构看一下。比如分子3到4，一个甲基提高了8x，文章提到这是一个rational design，通过减小羧基twist的能量penalty来提高活性。从分子2到3更是提高了50x，这里有两处改动，吲哚替换苯酚保留了氢键引入了疏水作用，右侧苯环取代的替换引起了临近Arg侧链翻转与苯环作用。总的来说是一个多重作用的结果。后面通过bioisostere替换羧酸并取得成功；之后右侧苯环引入新的取代，杂环与临近残基形成stacking及氢键，最终得到后面做药效的分子CAM2602。结合模式如下图A-C所示。正如可以预期的，这类分子表现出了非常好的激酶选择性。同时对Aurora B也有不错的选择性，如分子9可以达到1000x以上，与之前报道的选择性最好的Aurora A抑制剂相当或更好 (ATP口袋也有做到选择性上千倍的)。下图G是从结构分析对Aurora B选择性的原因。最后，in vitro及in vivo，PK and PD。总的来说CAM2602表现出良好的成药性，并展现出dose-dependent药效，虽然不及上临床的ATP口袋分子Alisertib。总的来说提供了一个PPI抑制剂从hit identification到优化至lead的案例，其中一些SAR也比较有意思。最后，如果回过头看比较早就已公布的Aurora A-TPX2肽段的复合物结构，有可能根据它就能锁定现在小分子结合的这个口袋，并评估其有一定的成药性，甚至可能in silico找到hit，virtual screening或基于structure-based modeling的design。maybe) Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents, J Med Chem, 2024 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

AACR会议临床1期临床终止临床结果

2024-09-27

·医药观澜

君实生物与微境生物合作开发！1类癌症新药获批临床

9月26日，中国国家药监局药品审评中心（CDE）官网最新公示，君实生物申报的WJ47156片获得临床试验默示许可，拟开发治疗晚期恶性肿瘤。根据君实生物此前公告介绍，WJ47156片（项目代号“JS125”）是其与微境生物医药合作开发的1类创新药，为一款靶向组蛋白去乙酰化酶（HDACs）抑制剂，属于表观遗传调控剂类药物。表观遗传学指的是一种可逆的遗传机制，它可以在不改变DNA序列的情况下，通过对DNA与组蛋白的修饰来影响基因表达，这是控制细胞分化和胚胎发育等关键生物过程的重要机制。HDACs参与组蛋白和非组蛋白赖氨酸残基乙酰化和去乙酰化动态平衡过程的调节，其表达已知与多种恶性肿瘤的发生与发展密切相关。据君实生物此前公告介绍，HDACs具有多种亚型，JS125可选择性对HDAC1、HDAC2、HDAC3产生抑制，并通过诱导细胞周期阻滞、抑制血管生成、调节免疫反应和促进癌症细胞衰老凋亡等来发挥抑制肿瘤作用，达到肿瘤治疗目的。此外有研究表明，HDACs还是癌症转移和转移相关的疗法耐药性之间的一个重要联系。HDACs在癌细胞中由于MAPK和JNK信号通路的激活而提高表达水平，控制与侵袭、生存和DNA修复相关的基因表达。开发选择性HDAC抑制剂可以影响与癌症转移和耐药性相关的多个信号通路。微境生物成立于2018年，该公司以研发抗肿瘤药为主，涉及免疫和代谢治疗领域。早在2020年，微境生物与君实生物就达成合作协议，在全球范围内就微境生物的四款在研抗肿瘤小分子药物（XPO1抑制剂、Aurora-A抑制剂、EGFR-exon20抑制剂、第四代EGFR抑制剂）进行共同开发、生产及商业化。公开资料显示，这4款产品目前均处于临床研究阶段。本次JS125获批临床，也意味着君实生物又一款癌症创新药进入临床研究阶段。根据君实生物官网，截至今年8月底，该公司还有近20款处于临床前研究阶段的抗肿瘤药物，靶点涵盖了CD112R+TIGIT、IL2+PD-1、EGFR+cMet、ATR、FGFR2、SHP2、IDH1、BCMA、Nectin4、Pan-CDK、IL-2、CD93等等。参考资料：[1]中国国家药监局药品审评中心官网.Retrieved Sep 26 , 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c [2]君实生物自愿披露关于JS125获得药物临床试验申请受理通知书的公告. Retrieved July 10，2024, From http://www.cninfo.com.cn/new/disclosure/detail?stockCode=688180&announcementId=1220589221&orgId=gfbj0833330&announcementTime=2024-07-10 [3]微境生物官网. From https://www.wigenbio.com/index.aspx [4]君实生物官网. From https://www.junshipharma.com/pipeline/#medical-content 内容来源于网络，如有侵权，请联系删除。

临床申请申请上市免疫疗法