A Cancer Research UK Phase I Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Aurora B Inhibitor GSK1070916A in Patients With Advanced Solid Tumors

RATIONALE: Aurora B/C kinase inhibitor GSK1070916A (GSK1070916A) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of GSK1070916A in treating patients with advanced solid tumors.

开始日期2010-03-01

申办/合作机构

Cancer Research UK

100 项与 Aurora C x Aurora B 相关的临床结果

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100 项与 Aurora C x Aurora B 相关的转化医学

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0 项与 Aurora C x Aurora B 相关的专利（医药）

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117

项与 Aurora C x Aurora B 相关的文献（医药）

2024-08-01·iScience

Spatio-temporal requirements of Aurora kinase A in mouse oocyte meiotic spindle building

Article

作者: Drutovic, David ; Blengini, Cecilia S ; Schindler, Karen ; Schier, Jan ; Vaskovicova, Michaela

Meiotic spindles are critical to ensure chromosome segregation during gamete formation. Oocytes lack centrosomes and use alternative microtubule-nucleation mechanisms for spindle building. How these mechanisms are regulated is still unknown. Aurora kinase A (AURKA) is essential for mouse oocyte meiosis because in pro-metaphase I it triggers microtubule organizing-center fragmentation and its expression compensates for the loss of the two other Aurora kinases (AURKB/AURKC). Although knockout mouse models were useful for foundational studies, AURK spatial and temporal functions are not yet resolved. We provide high-resolution analyses of AURKA/AURKC requirements during meiotic spindle-building and identify the subcellular populations that carry out these functions: 1) AURKA is required in early spindle assembly and later for spindle stability, whereas 2) AURKC is required in late pro-metaphase, and 3) Targeted AURKA constructs expressed in triple AURK knockout oocytes reveal that spindle pole-localized AURKA is the most important population controlling spindle building and stability mechanisms.

2024-07-01·Current Medicinal Chemistry

Recent Updates on Oncogenic Signaling of Aurora Kinases in Chemosensitive, Chemoresistant Cancers: Novel Medicinal Chemistry Approaches for Targeting Aurora Kinases

Review

作者: Bannimath, Gurupadayya ; Tengli, Anandkumar ; Baath, Ramandeep Kaur ; Kumari, Pooja ; Patil, Mayuri ; Beeraka, Narasimha Murthy

Abstract:The Aurora Kinase family (AKI) is composed of serine-threonine protein kinases involved in the modulation of the cell cycle and mitosis. These kinases are required for regulating the adherence of hereditary-related data. Members of this family can be categorized into aurora kinase A (Ark-A), aurora kinase B (Ark-B), and aurora kinase C (Ark-C), consisting of highly conserved threonine protein kinases. These kinases can modulate cell processes such as spindle assembly, checkpoint pathway, and cytokinesis during cell division. The main aim of this review is to explore recent updates on the oncogenic signaling of aurora kinases in chemosensitive/chemoresistant cancers and to explore the various medicinal chemistry approaches to target these kinases. We searched Pubmed, Scopus, NLM, Pubchem, and Relemed to obtain information pertinent to the updated signaling role of aurora kinases and medicinal chemistry approaches and discussed the recently updated roles of each aurora kinases and their downstream signaling cascades in the progression of several chemosensitive/chemoresistant cancers; subsequently, we discussed the natural products (scoulerine, Corynoline, Hesperidin Jadomycin-B, fisetin), and synthetic, medicinal chemistry molecules as aurora kinase inhibitors (AKIs). Several natural products' efficacy was explained as AKIs in chemosensitization and chemoresistant cancers. For instance, novel triazole molecules have been used against gastric cancer, whereas cyanopyridines are used against colorectal cancer and trifluoroacetate derivatives could be used for esophageal cancer. Furthermore, quinolone hydrazine derivatives can be used to target breast cancer and cervical cancer. In contrast, the indole derivatives can be preferred to target oral cancer whereas thiosemicarbazone-indole could be used against prostate cancer, as reported in an earlier investigation against cancerous cells. Moreover, these chemical derivatives can be examined as AKIs through preclinical studies. In addition, the synthesis of novel AKIs through these medicinal chemistry substrates in the laboratory using in silico and synthetic routes could be beneficial to develop prospective novel AKIs to target chemoresistant cancers. This study is beneficial to oncologists, chemists, and medicinal chemists to explore novel chemical moiety synthesis to target specifically the peptide sequences of aurora kinases in several chemoresistant cancer cell types.

2024-05-14·ACS Omega

Preclinical Evaluation of JAB-2485, a Potent AURKA Inhibitor with High Selectivity and Favorable Pharmacokinetic Properties

Article

作者: Chen, Mingming ; Cheng, Dai ; Wang, Yanping ; Yang, Guiqun ; Sun, Xin ; Wang, Yinxiang ; Li, Haijun ; Hu, Shizong ; Lin, Yiwei

As a critical mitotic regulator, Aurora kinase A (AURKA) is aberrantly activated in a wide range of cancers. Therapeutic targeting of AUKRA is a promising strategy for the treatment of solid tumors. In this study, we evaluated the preclinical characteristics of JAB-2485, a small-molecule inhibitor of AURKA currently in Phase I/IIa clinical trial in the US (NCT05490472). Biochemical studies demonstrated that JAB-2485 is potent and highly selective on AURKA, with subnanomolar IC₅₀ and around 1500-fold selectivity over AURKB or AURKC. In addition, JAB-2485 exhibited favorable pharmacokinetic properties featured by low clearance and good bioavailability, strong dose-response relationship, as well as low risk for hematotoxicity and off-target liability. As a single agent, JAB-2485 effectively induced G2/M cell cycle arrest and apoptosis and inhibited the proliferation of small cell lung cancer, triple-negative breast cancer, and neuroblastoma cells. Furthermore, JAB-2485 exhibited robust in vivo antitumor activity both as monotherapy and in combination with chemotherapies or the bromodomain inhibitor JAB-8263 in xenograft models of various cancer types. Together, these encouraging preclinical data provide a strong basis for safety and efficacy evaluations of JAB-2485 in the clinical setting.

项与 Aurora C x Aurora B 相关的新闻（医药）

2023-03-15

·PRNewswire

Jacobio Pharma to Present Data of Three Preclinical Studies at the 2023 AACR Annual Meeting

BEIJING and SHANGHAI and BOSTON, Mass., March 14, 2023 /PRNewswire/ -- Jacobin Pharma (1167.HK) today announced that the company will present the results of three preclinical studies of KRASmulti inhibitor JAB-23425, CD73-STING iADC JAB-X1800, and Aurora kinase A inhibitor JAB-2485 in form of the abstract during the American Association for Cancer Research (AACR) Annual Meeting 2023 (the "AACR 2023") from April 14 to 19, 2023. Details for the 2023 AACR abstracts are as follows: Abstract Number:1660 Abstract Title : Preclinical investigation of orally bioavailable, potent KRASMulti inhibitor JAB-23425 Session: Novel Antitumor Agents 4 Time: April 17, 2023, 9:00 AM – 12:30 PM (ET) KRASmulti inhibitor JAB-23425 targets multiple KRAS mutants in both RAS(ON) and RAS (OFF), with good selectivity over HRAS and NRAS. JAB-23425 has significant antitumor effect on cancer models with multiple KRAS mutations (such as G12D, G12V, and G13D) and amplification of wild type KRAS, and has no inhibitory effect on KRAS-independent cells. The KRASmulti inhibitor JAB-23425 is expected to solve the unmet clinical needs of patients with KRAS-mutated tumors. JAB-23425 is a leading compound of Jacobio's KRASmulti inhibitor. Abstract Number: 2923 Abstract Title : JAB-X1800: a potent immunostimulatory antibody-drug conjugate (iADC) targeting CD73 Session: Therapeutic Antibodies 2 Time: April 17, 2023, 1:30 PM – 5:00 PM (ET) JAB-X1800 is the world's first iADC by conjugating Jacobio's STING agonist to CD73 antibody, which is expected to turn the tumor from "cold" to "hot," and combine synergize with anti-PD-1 mAb. Abstract Number: 1645 Abstract Title: JAB-2485: a potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division Session : Novel Antitumor Agents 4 Time: April 17, 2023, 9:00 AM – 12:30 PM (ET) JAB-2485 is one of the top two highly selective Aurora A inhibitors with 1500-fold selectivity over Aurora kinase B and Aurora kinase C, with high activity and low bone marrow toxicity as well as favorable PK properties. "Jacobio leverages our IADDP (Induced Allosteric Drug Discovery Platform) to develop drugs aiming specific undruggable targets," said Dr. WANG Yinxiang, chairman and CEO of Jacobio, "These preclinical data are part of the research and development achievements of Jacobio since its establishment 8 years ago, and we will continue to transform the fundamental research in academia into clinical achievements through independent R&D in the future." The 2023 AACR Annual Meeting will be held in Orlando, Florida, USA from April 14th to April 19th. For more information, please visit the official website of the AACR: About Jacobio Jacobio(1167.HK) is committed to providing more products and solutions to people's health. Our mission is to provide compelling innovations for creating a pipeline of life-changing medicines. Our vision is to become a global leader recognized for our impact in drug R&D together with our partners. The company's R&D centers are located in Beijing, Shanghai and MA, with a platform and expertise in developing allosteric inhibitors against protein tyrosine phosphatase, KRAS and transcriptional factors. SOURCE Jacobio Pharma

AACR会议

2023-01-24

·CPHI制药在线

新药 | 加科思宣布完成首例患者给药，Aurora A抑制剂迎资本热捧

关注并星标CPHI制药在线加科思药业于近日宣布，其自主研发的全球首创新药Aurora A（极光激酶A）抑制剂JAB-2485的I期临床研究在美国完成晚期实体瘤患者首例给药。临床前数据表明，JAB-2485在生化和细胞水平上具有高选择性，JAB-2485对Aurora A的抑制活性比对Aurora B的抑制活性高一千多倍，有潜力使小细胞肺癌、三阴乳腺癌等肿瘤患者受益。作为一种高选择性小分子Aurora A抑制剂，JAB-2485在细胞水平可以抑制Aurora A活性，诱导细胞凋亡，抑制肿瘤生长。 Aurora A也叫做极光激酶A，同时作用于MYC和Rb两条信号通路，适用于治疗Rb1基因缺失的肿瘤患者。Rb是一种抑癌基因，相当于细胞增殖过程中的“刹车”，当“刹车”发生突变后会失灵，造成细胞持续分裂，这就是癌症的成因。当前，Aurora A研发进展到哪一步了？Aurora激酶有什么功能？细胞周期调控因子Aurora Aurora激酶家族主要参与细胞有丝分裂的调控，其功能的丧失会影响细胞正常分裂，如影响胚胎发育的过程等。而如果这类激酶表达过于活跃，则会引起细胞分裂失控，导致癌症的发生。 Aurora激酶家族成员包括Aurora A、Aurora B和Aurora C，其中Aurora A/B在人体中广泛表达，而Aurora C主要在睾丸组织中表达。Aurora-A和Aurora-B虽然在序列水平上有一定的相似性，但它们的定位和功能在很大程度上是不重叠的。 Aurora A是Aurora激酶家族的重要成员。它在有丝分裂的G2/M期发挥重要作用，主要影响中心粒成熟、纺锤体形成等过程。Aurora A从细胞分裂的S期开始定位于复制的中心粒，随后被上游信号激活，启动细胞进入有丝分裂，并在G2/M转换阶段达到表达量和活性最高。同时在有丝分裂末期，Aurora A会被降解，直至新一轮细胞分裂启动。而在癌细胞中，Aurora A发生过表达或突变现象，而且Aurora A可以通过磷酸化调控多种起到抑癌作用的蛋白，包括P53和BRAC2等关键角色。Aurora A通过磷酸化Ser215和Ser315位点，抑制P53转录活性并增加降解，并且在乳腺癌、卵巢癌等癌种中被发现抑制BRAC2表达。虽然Aurora A在肿瘤的发生发展过程中意义重大，但其抑制剂的研发并非一帆风顺。 Aurora A抑制剂，进展并不顺利多项研究已证明Aurora A的过度表达与多种癌症的发生相关。而Aurora A抑制剂能够抑制肿瘤细胞的增殖、转移等，已成为细胞周期领域抗肿瘤靶向药物的研究热点。但是Aurora A抑制剂的研发并不顺利，在过去十年，先后有20余个Aurora A激酶抑制剂由于QT间期延长、骨髓抑制、嗜睡等毒副作用、患者受益有限等原因以临床失败而告终。目前全球尚无Aurora A激酶抑制剂获批上市。 2008年，武田斥资88亿美元，以53%的溢价将美国Millennium Pharmaceuticals公司收购，获得其Aurora A抑制剂候选药物——Alisertib。但是截至目前，武田研发管线中已不再更新这一项目信息。后来研究者发现，在第一代Aurora A抑制剂研发中，研究者把目光聚焦在泛抑制剂领域，它们对Aurora A和B都有抑制作用，结果由于选择性不高，副作用严重，往往伴随着严重的骨髓抑制毒性。于是，研究者们开始转向高选择性Aurora A抑制剂的研发。这类高选择性Aurora A抑制剂骨髓毒性降低，选择性较强。随着高选择性Aurora A抑制剂的出现，这一赛道重新获得资本热捧。全球在研Aurora A抑制剂 2018年，礼来以1.1亿美元首付款和4.65亿美元监管销售里程金的方式收购AurKa Pharma公司，获得其高选择性Aurora A抑制剂AK01，这款药物当时处于I期临床阶段，正在开展与奥希替尼联用治疗EGFR突变晚期转移性非鳞NSCLC的研究。目前，AK01正在开展针对Rb缺失广泛期小细胞肺癌、接受CDK4/6抑制剂联合内分泌疗法治疗后的转移性乳腺癌、复发难治成神经细胞瘤和其他实体瘤的临床I期研究。除礼来外，国内外一众药企也都投入到高选择性Aurora A抑制剂的研发中。目前全球在研Aurora A抑制剂（根据公开资料整理） ENMD-2076由Miikana Therapeutics研发，其作用机理为通过靶向Aurora A并抑制其活性，导致STAT3磷酸化水平下降，进而促进肿瘤细胞内趋化因子基因CXCL10和CXCL11的高表达。通过体外和小鼠模型实验发现，ENMD-2076通过激活肿瘤细胞趋化因子CXCL10和CXCL11的基因表达和分泌，来吸引更多的、对肿瘤具有杀伤作用的CD8+?T细胞进入肿瘤微环境，改变肿瘤微环境的免疫状态。另外，ENMD-2076与PD-1抗体联用，更有效抑制了三阴性乳腺癌在动物模型中的生长，提高了肿瘤免疫治疗的响应率。 TT-00420是药捷安康（南京）科技股份有限公司的核心产品，其通过抑制Aurora A和Aurora B以及参与血管生成的受体酪氨酸激酶表现出双重机制抑制肿瘤的增殖。 TT-00420在I期临床研究中展现了良好的安全性，目前已经在全球开展了多项肿瘤临床试验，试验中心包括MD Anderson Cancer Center、中国医学科学院肿瘤医院等。2019年，TT-00420获得了FDA授予的治疗胆管癌的孤儿药认证。 TAS119是由日本Taiho Pharmaceutical研发的一款高选择性Aurora A抑制剂。2020年6月，国内公司捷思英达宣布从Taiho引进TAS-119在肿瘤领域的全球独家开发和商业化权利。目前，TAS-119已在美国和欧洲完成了两项I期临床研究。 WJ05129是由微境生物研发的一种Aurora A抑制剂。它与RB1基因缺失或失活具有合成致死的效果，可以用于治疗小细胞肺癌和三阴乳腺癌等RB1 缺失或失活的恶性肿瘤。2020年，微境生物与君实生物签订了一份技术转让及合作协议，将包括WJ05129在内的4个药物项目50%的权益转让给了君实生物。作为新兴的抗癌靶标，Aurora激酶引起了不少研究机构和企业的兴趣。初代Aurora抑制剂大多是泛抑制剂，在疗效和安全性上存在欠缺。如今开发高选择性的Aurora A抑制剂成为了Aurora激酶靶向药物的研发趋势。目前这一赛道尚无药物获批上市，布局企业不多。对于国内药企来说，或许这是一种差异化的临床开发策略。参考来源： 1.Katsha, A., Belkhiri, A., Goff, L. et al. Aurora kinase A in gastrointestinal cancers: time to target. Mol Cancer 14, 106 (2015). https://doi.org/10.1186/s12943-015-0375-4. 2.Bavetsias V, Linardopoulos S. Aurora Kinase Inhibitors: Current Status and Outlook. Front Oncol. 2015 Dec 21;5:278. doi: 10.3389/fonc.2015.00278. PMID: 26734566; PMCID: PMC4685048. 3.Sootome H, Miura A, Masuko N, Suzuki T, Uto Y, Hirai H. Aurora A Inhibitor TAS-119 Enhances Antitumor Efficacy of Taxanes In Vitro and In Vivo: Preclinical Studies as Guidance for Clinical Development and Trial Design. Mol Cancer Ther. 2020 Oct;19(10):1981-1991. doi: 10.1158/1535-7163.MCT-20-0036. Epub 2020 Aug 11. PMID: 32788206. 4.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539775/. 来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床结果临床1期AACR会议