小分子 c-Met 激酶抑制剂的研究进展

c-Met 激酶与肿瘤的发生、发展和转移密切相关。c-Met 激酶小分子抑制剂的研究为多种类型肿瘤提供了一种新的靶向治疗手段。该文重点介绍近年来报道的不同结构类型的 c-Met 激酶小分子抑制剂，并对其活性和构效关系进行综述。     

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。     

一种创新型的小分子抗肿瘤药物的开发进展

目的是开发一种创新型的小分子抗肿瘤药物,属于国际最新型的针对靶标分子而设计的小分子化学合成药物。此药能选择性地抑制VEGFR2受体酪氨酸激酶,阻断肿瘤血管生成,血液供给;抑制肿瘤生长,从而达到有效地抑制原发肿瘤的生长的目的。在VEGFR2高度表达的非小细胞肺癌中,此药具有明显的肿瘤抑制作用。     

新型多激酶抑制药regorafenib作用机制及临床研究概述

Regorafenib是一种新型的多激酶抑制药,对于细胞因子受体(KIT)、原癌基因(RET)、血小板源性生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)和血管内皮生成因子(VEGFR)等多个肿瘤通路均有抑制作用,临床试验证实对多种实体瘤有效,美国FDA已批准用于晚期直肠癌治疗,是第一个在晚期结直肠癌中被证实有效的口服多激酶抑制药.本文就其药理学、药动学、不良反应、相互作用及临床试验做一综述.     

表皮生长因子受体酪氨酸激酶抑制剂BPI-2009的抗肿瘤作用及其机制的研究

目的:探讨一种口服的表皮生长因子受体(epidermalgrowthfactorreceptor ,EGFR)酪氨酸激酶抑制剂(BPI 2 0 0 9)的抗肿瘤作用及其机制。方法:Westernblot方法检测BPI 2 0 0 9对酪氨酸激酶和EGFR自动磷酸化的抑制作用,MTT法检测BPI 2 0 0 9对多种肿瘤细胞的生长抑制作用,使用A4 31肿瘤模型的荷瘤裸鼠进行体内的肿瘤抑制试验。结果:通过对EGFR激酶抑制剂化学文库的筛选,发现BPI 2 0 0 9是一个有效的EGFR激酶抑制剂。BPI 2 0 0 9对EGFR激酶的半数抑制浓度(IC50 )为5nmol·L- 1,当其浓度达到6 2 .5nmol·L- 1的时候可以完全抑制EGFR激酶的活性,但在10 0nmol·L- 1时对Abl、Abl相关基因(Abl relatedgenes ,Arg)以及c- Src酪氨酸激酶都没有明显的抑制作用。BPI 2 0 0 9可以阻断EGFR介导的细胞内蛋白酪氨酸的磷酸化,IC50 为4 5nmol·L- 1。在肿瘤细胞生长抑制试验中,BPI 2 0 0 9对于肿瘤细胞的生长抑制作用与EGFR在细胞中的表达密切相关。人类肿瘤细胞A4 31移植瘤抑制试验的研究表明BPI 2 0 0 9经口给药每天1次在10 0mg·kg- 1,肿瘤抑制率达6 4% ,有明显的剂量效应关系,并没有发现明显的病态和体重下降。结论:BPI 2 0 0 9是一种有效的高选择性的以EGFR酪氨酸激酶为靶点的抗肿瘤药物。     

酪氨酸激酶类抗肿瘤作用靶点的研究进展

酪氨酸激酶作为抗肿瘤靶点研究广泛,效果良好,在抗肿瘤领域具有广阔的应用前景。目前已发现的蛋白酪氨酸激酶包括20余个受体酪氨酸激酶家族和10余个非受体酪氨酸激酶家族,他们与肿瘤的发生和发展关系密切。本文主要根据近3年的文献,结合酪氨酸激酶与肿瘤的关系,对酪氨酸激酶类靶点及其抑制剂的研究进展作一综述。     

Aurora激酶及其抑制剂研究状态综述

Aurora激酶家族是苏氨酸/丝氨酸激酶,在有丝分裂的染色体排列,分离和胞质分裂中起重要作用。最近的研究发现,Aurora激酶在大量人类实体瘤和血液恶性肿瘤中过表达,表明其是开发抗肿瘤药物的重要靶点。本文就近几年国内外对Aurora激酶的研究,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。     

黏着斑激酶及其小分子抑制剂作为抗肿瘤药物的研究进展

抗黏着斑激酶是一种非受体型酪氨酸蛋白激酶,在许多肿瘤的发生和发展过程中均有过表达。研究表明,作为细胞内重要的骨架蛋白和调节多种细胞信号通路的关键分子,黏着斑激酶在肿瘤发生、发展、迁移和侵袭的各个阶段都起着重要作用。因此,以黏着斑激酶作为抗肿瘤靶点开发其抑制剂的研究受到广泛关注。综述黏着斑激酶的结构与功能、它与肿瘤的关联及其小分子抑制剂的研究与开发。     

小分子PIM激酶抑制剂的研究进展

PIM激酶家族在各类肿瘤中高表达,并对肿瘤的发生发展起着重要的调节作用,闪此PIM激酶有望成为抗癌药物的新靶点,小分子PIM激酶抑制剂具有良好的应用前景。本文从PIM激酶家族蛋门结构、在肿瘤发生发展中的作用途径以及小分子PIM激酶抑制剂的研究进展j个方面进行综述。     

抗癌药Tovok^TM

Tovok^TM（BIBW-2992）是勃林格殷格翰公司开发的表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）酪氨酸激酶的强效、不可逆的双重抑制剂,口服有效。用荷瘤小鼠进行的研究显示,本品对某些肿瘤如鳞状细胞癌A-431、乳腺癌MDA—MB-453、胃癌NCL-N87及卵巢癌SK—OV-3的生长具有强效持久的抑制作用。     

Receptor tyrosine kinases: the main targets for new anticancer therapy

Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors.     

Change in the activity of the cyclic AMP-dependent protein kinase in antigen-stimulated sensitized mast cells and effect of drugs inhibiting allergic mediator release

The activity of cyclic AMP-dependent protein kinase (protein kinase A) in the sensitized rat mast cell was decreased 2 min after antigen challenge when the histamine release exhibited a maximum. Drugs inhibiting allergic mediator release such as disodium cromoglycate, tranilast and theophylline significantly inhibited antigen-induced histamine release and reduced a decrease in the activity of protein kinase A. These results suggest that protein kinase A is involved in the histamine releasing process in the mast cell, and drugs inhibiting allergic mediator release cause their effects partially through the inhibition of protein kinase A.     

The strange connection between epidermal growth factor receptor tyrosine kinase inhibitors and dapsone: from rash mitigation to the increase in anti-tumor activity

The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion.     

表皮生长因子受体酪氨酸激酶抑制剂在肿瘤治疗中的应用

表皮生长因子受体 (EGFR)酪氨酸激酶 ,是细胞外信号传递到细胞内的重要枢纽 ,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用 ,在多种癌细胞中过度表达。许多研究表明 ,抑制EGFR酪氨酸激酶活性 ,可抑制肿瘤生长。目前 ,已有几种EGFR酪氨酸激酶抑制剂进入了临床试验。本文对几种EGFR酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究进展做一综述。     

Naringin suppresses the development of glioblastoma by inhibiting FAK activity

As the most common and lethal primary malignant brain cancer, glioblastoma is hard to timely diagnose and sensitive therapeutic monitoring. It is essential to develop new and effective drugs for glioblastoma multiform. Naringin belongs to citrus flavonoids and was found to display strong anti-inflammatory, antioxidant and antitumor activities. In this report, we found that naringin can specifically inhibit the kinase activity of FAK and suppress the FAK^p-Try397and its downstream pathway in glioblastoma cells. Our study showed out that naringin can inhibit cell proliferation by inhibiting FAK/cyclin D1 pathway, promote cell apoptosis through influencing FAK/bads pathway, at the same time, it can also inhibit cell invasion and metastasis by inhibiting the FAK/mmps pathway. All these showed that naringin exerts the anti-tumor effects in U87?MG by inhibiting the kinase activity of FAK.     

Ethanol-mediated inhibition of mitogen-activated protein kinase phosphorylation in mouse brain

Ethanol (1.5-3.5 g/kg body weight) was administered intraperitoneally to mice and the phosphorylation of MAP (mitogen-activated protein) kinase in the cerebral cortex was determined using phospho-specific MAP kinase antibodies. Ethanol inhibited the phosphorylation of MAP kinase in a dose- and time-dependent manner. Developmental studies demonstrated that the levels of phospho-MAP kinase increased from fetal cortex (prenatal) to 16-day-old mice (postnatal) and remained constant up to 4 months of age. However, ethanol (3.5 g/kg) decreased the phospho-MAP kinase staining in all of the age groups studied. Subcellular fractionation studies demonstrated that ethanol inhibited the phosphorylation of MAP kinase in both the cytosol as well as nucleus, but did not alter the levels of MAP kinase. Likewise, MK-801 (0.4 mg/kg) or flurazepam (75 mg/kg) also decreased the phospho-MAP kinase content. These data indicate that ethanol may inhibit the phosphorylation of MAP kinase in vivo by either inhibiting NMDA receptors or activating GABA receptors.     

New indolocarbazoles as antitumour active compounds: evaluation of the target by experimental and theoretical studies

A series of indolocarbazoles was synthesized as congeners of the natural lead compounds rebeccamycin (1) and staurosporine (2) which reduce cell growth by inhibiting topoisomerase I and protein kinase C respectively. Two of the carbazoles (3 and 4) screened at the National Cancer Institute (NCI, USA) showed an interesting cytotoxic activity and were therefore further analysed. The mechanism of action of these two compounds was studied experimentally using different assay to determine the B-DNA binding ability and the inhibition of topoisomerase I and of protein kinase C. Theoretical molecular modelling studies were also performed to describe the possible interactions with protein kinase C and DNA.     

Design,Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs

Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader 9 was discovered, and it effectively inhibited the activation of downstream NF-κB signaling and outperformed the parent compound 1. In addition, compound 9 displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound 1. These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.     

VEGFR酪氨酸激酶抑制剂的临床应用与研究进展

血管内皮生长因子（ VEGF ）可诱导肿瘤的血管新生,在肿瘤生长中起到了关键作用。抑制血管内皮生长因子受体（ VEGFR）酪氨酸激酶能在一定程度上抑制肿瘤的生长, VEGFR酪氨酸激酶抑制剂已成为现在研究的热点之一。该文对VEGF和VEGFR进行了简要介绍,并简述了VEGFR酪氨酸激酶抑制剂的临床应用和主要化学结构类型。     

7,8-dichloro-1-oxo-β-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes

Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-β-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.