Aurora激酶抑制剂研究进展

Aurora激酶是细胞有丝分裂相关的一类丝氧酸/苏氨酸激酶,在细胞周期调控中起着重要的作用,研究发现Aurora激酶在多数血液恶性肿瘤和实体瘤中均高表达,表明Aurora激酶是抗肿瘤药物研究的重要新靶点之一.本文主要围绕Aurora家族的三个成员,对其生物学功能及其与肿瘤的关系、抑制剂的研究进展及其研究策略进行综述.     

肿瘤治疗靶向药物Aurora激酶抑制剂

Aurora激酶在肿瘤细胞的有丝分裂进程中起着重要的调控作用,从而影响细胞周期进程,是抗肿瘤药物的新靶点。本文就Aurora激酶在肿瘤细胞生长中所起的作用及现阶段的Aurora激酶抑制剂进行系统介绍。     

Aurora激酶抑制药研究进展

Aurora激酶是近年来发现的新型抗肿瘤靶点,它在肿瘤的发生发展中起到至关重要的作用。该文从Aurora激酶作为抗肿瘤靶点的意义,Aurora-A激酶特异性抑制药及临床应用,Aurora-B激酶特异性抑制药及临床应用,Pan-Aurora激酶特异性抑制药及临床应用等几个方面,对Aurora激酶抑制药的研究进展进行论述,期望能够对临床工作者有所帮助。     

Aurora激酶及其抑制剂研究进展

Aurora激酶的三种亚型Aurora-A、Aurora-B、Aurora-C是细胞有丝分裂的重要调节因子,近年来成为癌症治疗的热门靶点.本文重点介绍Aurora激酶三种亚型与肿瘤的关系,以及Aurora激酶抑制剂的最新研究进展和研究方向.     

Aurora激酶及其抑制剂的研究进展

恶性肿瘤是威胁人类生命健康的重大难治性疾病,人类在恶性肿瘤的治疗过程中经历了漫长的历史变迁。Aurora激酶家族是苏氨酸/丝氨酸激酶,是细胞有丝分裂期重要的调节因子,可影响细胞周期进程,是抗肿瘤药物的新靶点。本文简要对Aurora激酶的生物学功能、与肿瘤的关系及其抑制剂的研究进展进行综述。     

Aurora激酶及其抑制剂的研究进展

目的 从结构出发介绍Aurora激酶及其抑制剂的研究进展。方法 总结 Aurora激酶抑制剂骨架特征和结合模式,以及进入临床的Aurora激酶抑制剂的研究进展。结果和结论 Aurora激酶家族是肿瘤治疗的一个新兴靶标。腺嘌呤骨架可能是设计高活性Aurora激酶抑制剂的重要母核。     

Aurora激酶抑制剂的研究进展

在有丝分裂的过程中,Aurora激酶参与纺锤体形成,中心体成熟,染色体分化和胞质分裂.Aurora激酶的过度表达或分化易导致有丝分裂异常,与形成肿瘤的基因组不稳定性密切相关.以Aurora激酶为靶点设计、合成的药物已成为近年来肿瘤药物治疗的研究热点.本文综述了已经进入临床研究的Aurora小分子抑制剂在临床前、临床的研究进展.     

Aurora激酶抑制剂研究进展

Aurora激酶家族是细胞有丝分裂期重要的调节因子,可影响细胞周期进程,是抗肿瘤药物的新靶点。简述Aurora激酶的生物学和与肿瘤发生发展的关系,重点介绍Aurora激酶抑制剂的结构类型和构效关系。     

Aurora激酶抑制剂的结构优化策略

Aurora激酶是一种丝氨酸/苏氨酸蛋白激酶,在肿瘤细胞的有丝分裂进程中起着重要的调控作用。因此,以该激酶为靶点,开发新型抗肿瘤药物,已成为研究热点。从提高化合物的活性和选择性、增加其水溶性及改善其药动学性质等方面,综述Aurora激酶抑制剂的结构优化策略。     

Aurora-A激酶及多重酪氨酸蛋白激酶抑制剂类抗癌药ENMD-2076

由EntreMed公司开发的抗癌药ENMD-2076是口服有效的Aurora激酶和多重酪氨酸激酶抑制剂。Aurora激酶在细胞增殖过程中起重要作用,人类Aurora激酶有3种亚型：Aurora-A、-B和-C,它们虽具明显的序列同源性,但在细胞中所处区域和功能各异。其中,Aurora-A激酶在中心体复制期间细胞退出有丝分裂后定位于中心体,     

A Dual Non‐ATP Analogue Inhibitor of Aurora Kinases A and B,Derived from Resorcinol with a Mixed Mode of Inhibition

Aurora kinases are the most commonly targeted mitotic kinases in the intervention of cancer progression. Here, we report a resorcinol derivative, 5‐methyl‐4‐(2‐thiazolylazo) resorcinol (PTK66), a dual inhibitor of Aurora A and Aurora B kinases. PTK66 is a surface binding non‐ATP analogue inhibitor that shows a mixed pattern of inhibition against both of Aurora A and B kinases. The in vitro IC₅₀ is approximately 47 and 40 μm for Aurora A and Aurora B kinases, respectively. In cellular systems, PTK66 exhibits a substantially low cytotoxicity at micromolar concentrations but it can induce aneuploidy under similar dosages as a consequence of Aurora kinase inhibition. This result was corroborated by a drop in the histone H3 (S10) phosphorylation level detected via Western blot analysis using three different cell types. Altogether, our findings indicate that the ligand containing resorcinol backbone is one of the novel scaffolds targeting the Aurora family of kinases, which could be a target for antineoplastic drug development.     

A small molecule identified through an in silico screen inhibits Aurora B–INCENP interaction

Aurora B is a serine/threonine kinase that has a central role in the regulation of mitosis. The observation of Aurora B overexpression in cancer makes it a promising target to develop antitumoral inhibitors. We describe a new potential inhibitor that exclusively targets the interaction site of Aurora B and its activator INCENP. We performed a structure‐based virtual screening and determined five potential candidates of 200 000 compounds, which selectively bind to the Aurora B::INCENP interaction site, but not to the ATP‐binding site (kinase pocket) of Aurora B or other related kinases. Further characterization in vivo validated the inhibitory role of one of these five compounds in Aurora B::INCENP complex formation and exhibited hallmarks of Aurora inhibition such as chromosome congression and segregation defects that interfere with the progression into cytokinesis and result in multinuclear cells. Our results provide an alternative approach on the way of exploring specific kinase inhibitors.     

An update on the pharmacokinetics and pharmacodynamics of alisertib,a selective Aurora kinase A inhibitor

Human Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bio‐orientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation. AURKA has been found to be overexpressed in various solid and haematological cancers and has been linked with poor prognosis. Its important role in cancer initiation, growth, and metastasis has brought the focus to search for potent and selective AURKA inhibitors for cancer treatment. MLN8237, also known as alisertib, is one selective AURKA inhibitor that has shown remarkable anticancer effects in preclinical studies. Alisertib exhibits favourable pharmacokinetic properties. Alisertib has generally showed good partial response rates of 4–52% and good safety profiles in Phase I and II trials when it is solely administered as well as combined with cytotoxic chemotherapeutic drugs. Recently, the multicentre, randomized Phase III study of alisertib in patients with relapsed or refractory peripheral T‐cell lymphoma has been discontinued due to unsatisfactory efficacy. The low risk of side effects, accessibility, and effectiveness of alisertib makes it a new promising anticancer therapy and further mechanistic and clinical studies are warranted.     

Aurora kinase targeted therapeutics in oncology: past,present and future

Aurora A, B and C are a family of serine-threonine protein kinases that regulate distinct functions of the mitotic phase of the cell cycle. All three Auroras are overexpressed in human cancers with an associated polyploid phenotype. Crystal structures of Aurora A or B with bound small molecular inhibitors have provided detailed insight of the active site, mode of binding and hotspots for developing resistance through point mutations. Structural studies have aided fragment-based rational drug discovery of Aurora inhibitors, including compounds specific for Aurora A or B. Aurora inhibitors have excellent antitumor activity in rodent models of cancer. At present, Aurora inhibitors are being evaluated in Phase I trials. The future holds promise for rational combinations in both solid and hematological malignancies.     

Targeting cell cycle kinases and kinesins in anticancer drug development

The cell cycle is regulated by kinases such as the cyclin-dependent kinases (CDKs) and non-CDKs, which include Aurora and polo-like kinases, as well as checkpoint proteins. Mitotic kinesins are involved in the establishment of the mitotic spindle formation and function, and also play a role in cell cycle control. The disruption of the cell cycle is a hallmark of malignancy. Genetic or epigenetic events result in the upregulation of these kinases and mitotic kinesins in a myriad of tumour types, suggesting that their inhibition could result in preferential targeting of malignant cells. Such findings make the development of these inhibitors a rational and attractive new area for cancer therapeutics. Although challenges of potency and non-specificity have hampered their progress through the clinic, several novel compounds are presently in various phases of clinical trial evaluation.