胰岛素样生长因子-1受体和胰岛素受体双重抑制剂类抗癌药Linsitinib

胰岛素样生长因子-1(IGF-Ⅰ)受体是一种跨膜受体酪氨酸激酶,与许多人类肿瘤的发生发展密切相关,由胞外α亚单位和含跨膜及胞内区部分的β亚单位构成,其中α亚单位负责与IGF-Ⅰ和-Ⅱ等可溶性IGF-Ⅰ受体配体结合,而β亚单位则发挥胞内受体酪氨酸激酶作用.与配体结合后,IGF-Ⅰ受体的同源二聚体和IGF-Ⅰ受体-受体酪氨酸激酶的异源二聚体便自身磷酸化,并激活下游PI3K/Akt/丝氨酸-苏氨酸蛋白激酶雷帕霉素靶蛋白(mTOR)和Ras/有丝分裂原活化蛋白激酶(MAPK)等信号通路,最终抑制细胞凋亡,促进细胞生长和迁移,导致肿瘤的生长和转移.     

EphB2受体及其配体在肿瘤癌变中作用的研究进展

<正>肿瘤的发生及演变与细胞内信号转导异常有着密切的关系。其中酪氨酸蛋白激酶受体(receptor of tyrosine kinase,RTK)在信号传导中的作用尤为重要。Eph(erythropoietin-producing hepatoma cell line)家族是最大的酪氨酸蛋白激酶     

蛋白酪氨酸激酶信号转导途径与抗肿瘤药物

细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用，肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(protein tyrosine kinases，PTKs)介导的信号转导途径，分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径，非受体酪氨酸激酶介导的Src、Bcr-Abl和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点，统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。     

血小板源生长因子受体抑制剂的研究近况

近年来的研究发现，酪氨酸蛋白激酶水平的升高已成为细胞增殖恶变的标志之一，其特异性的抑制剂对肿瘤有较高的预防及治疗价值。本文着重阐述了酪氨酸蛋白激酶受体中的血小板源生长因子受体抑剂的作用机制、分类、构效关系及上市药物等新进展。     

GABA_A受体的细胞内调控及其机制

除了通过受体复合体上特有的结合位点接受多种结构不同的物质的变构调控外,GABA_A受体的另一个显著特点是受多种内源性物质如Ca（2+）,三磷酸腺苷,蛋白激酶A,蛋白激酶C,酪氨酸激酶和钙调素依赖性蛋白激酶Ⅱ等的调控。GABA_A受体的细胞内调控对控制神经元兴奋性可能有重要影响。     

阿片受体对呼吸功能影响的研究进展

<正>阿片受体的研究已有40年历史。阿片受体及其内源性阿片肽分布于大脑和外周组织,在调节内分泌、心血管、疼痛、呼吸、应激反应、体温调节、胃肠和免疫功能等方面起着重要的作用。阿片类物质与阿片受体结合后,通过蛋白激酶、钙、钾通道、钙调蛋白激酶Ⅱ、G蛋白偶联受体激酶和丝裂原激酶等复杂而庞大的信号转导及调节控制系统进行转     

EGFR酪氨酸激酶及其抑制剂的研究进展

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,并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。本文对EGFR酪氨酸激酶及其几种小分子抑制剂在肿瘤治疗中的研究进展作一综述。     

巨噬细胞集落刺激因子受体激酶及其抑制剂的研究进展

巨噬细胞集落刺激因子受体（c-Fms）是原癌基因c-fms的编码产物,属于Ⅲ型受体酪氨酸激酶家族成员。巨噬细胞集落刺激因子与c-Fms结合,激活其酪氨酸激酶,在单核巨噬细胞系的存活、增殖、分化以及胚胎发育过程中发挥着重要的作用。c-Fms及其配体的过度表达,引起该受体介导的细胞信号通路异常激活,参与了肿瘤形成和炎症发生过程。因此,靶向c-Fms激酶的抑制剂能抑制受体的磷酸化,阻断受体介导的细胞信号通路,是治疗肿瘤、关节炎等疾病的潜在药物。     

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。     

Snapin与TrkA相互作用对神经递质释放影响的研究

神经营养素能够影响脊椎动物神经元的增殖、分化、凋亡、存活等生命过程,但其功能的发挥则需要Trk和p75NTR两种膜受体的存在。TrkA受体是一种酪氨酸激酶受体,同其它酪氨酸激酶受体一样,其受体膜内区的酪氨酸磷酸化后,可以被其它信号分子识别,为信号的传导提供有关蛋白的募集位点。肝细胞生长因子的受体Met也是一种酪氨酸激酶受体,它的酪氨酸激酶区同TrkA相比具有37％的同源性,有报道发现Met与神经递质释放和内分泌过程中的一个关键调节蛋白——Snapin有相互作用,且Trk受体可以调节突触囊泡的胞吞和胞吐的过程,影响神经递质受体的活性,所以我们推测Snapin和TrkA之间也可能存在相互作用。在此前提下我们开展了一系列实验并且取得了初步的实验结果,通过酵母双杂交实验验证了TrkA的功能区TrkAICD、TrkA—ATP、TrkA-775、TrkA-790均能够与Snapin相互作用,免疫共沉淀实验也证明了TrkAICD与Snapin能够相互作用。     

Interactions between Src family protein tyrosine kinases and PSD-95

Five members of the Src family of non-receptor protein tyrosine kinases--Lck, Lyn, Fyn, Src, and Yes--are known to be expressed in the central nervous system. Src and Fyn have been shown to play important roles in synaptic transmission and plasticity at excitatory synapses. Here we investigate the subcellular distribution and potential binding partners of Src family protein tyrosine kinases in brain, focusing on the lesser studied kinases Lck, Lyn, and Yes. We find that Lck, Lyn, and Yes are localized to the postsynaptic density (PSD), the primary structural component of excitatory synapses. Lyn and Yes, as well as Src, but not Lck physically associate with the prominent PSD scaffolding protein PSD-95 in co-immunoprecipitation experiments. Further, we demonstrate that PSD-95 GST fusion proteins bind directly to purified recombinant Lyn, Src, and Yes in vitro. In addition, we show that PSD-95 is unique among PSD-95 family members in that the other members, PSD-93, SAP97, and SAP102, do not physically associate with Lyn, Src, or Yes. Together our results suggest that PSD-95 may be important for localizing and/or regulating multiple Src protein tyrosine kinases at the NMDA receptor multiprotein complex.     

酪氨酸激酶抑制剂类新药的研发现状

蛋白激酶在多种疾病,特别是肿瘤发生发展过程中起重要作用,以其为药物靶点的激酶抑制剂则成为近年药物研发的热点。目前已有11个小分子激酶抑制剂上市,其中9个为酪氨酸激酶抑制剂。激酶抑制剂具有高选择性、副作用少的特点。已上市药物已经在慢性粒细胞白血病、非小细胞肺癌、肾细胞癌等多种疾病的治疗中显示出其较传统治疗药物的优越性,部分已成为治疗肿瘤的一线用药。本文对小分子酪氨酸激酶抑制剂类新药的研发现状进行综述。     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

Synthetic Tyr-phospho and non-hydrolyzable phosphonopeptides as PTKs and TC-PTP inhibitors*

Tyrosine-specific protein kinases and phosphatases are important signal transducing enzymes in normal cellular growth and differentiation and have been implicated in the etiology of a number of human neoplastic processes. In order to develop agents which inhibit the function of these two classes of enzymes by interfering with the binding of their substrates, we synthesized analogs derived from the peptide EDNEYTA. This sequence reproduces the main autophosphorylation site of Src tyrosine kinases. In this work we report the synthesis, by classical solution methods, of the phosphotyrosyl peptide ED-NEYpTA as well as of three analogs in which the phosphotyrosine is replaced by a phosphinotyrosine and by two unnatural, non-hydrolyzable amino acids 4-phosphonomethyl-l -phenylalanine and 4-phosphono-l -phenylalanine. The Src peptide and its derivatives were tested as inhibitors of three non-receptor tyrosine kinases (Lyn, belonging to the Src family, CSK and PTK-IIB) and a non-receptor protein tyrosine phosphatase obtained from human T-cell (TC-PTP). The biomimetic analogues, which do not significantly affect the activity of CSK, PTK-IIB and TC-PTP, act:is efficient inhibitors on Lyn, influencing both the exogenous phosphorylation and, especially, its autophosphorylation. In particular, the Pphe derivative may provide a basis for the design of a class of inhibitors specific for Lyn and possibly Src tyrosine kinases, capable of being used in vivo and in vitro conditions. © Munksgaard 1995.     

Therapeutic targeting of receptor tyrosine kinases in lung cancer

Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.     

Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.     

Tyrosine kinases as targets in cancer therapy – successes and failures

Protein kinases play a crucial role in signal transduction and also in cellular proliferation, differentiation and various regulatory mechanisms. The inhibition of growth-related kinases, especially tyrosine kinases, might therefore provide new therapies for diseases such as cancer. Due to the enormous progress that has been made in the past few years in the identification of the human genome, in molecular and cell biology technologies, in structural biology and in bioinformatics, the number of receptor and non-receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased. Currently, more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology. The progress made in the crystallisation of protein kinases, in most cases complexed with ATP-site-directed inhibitors, has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design; more than 20 ATP-competitive, low molecular weight inhibitors are in various phases of clinical evaluation. Meanwhile, clinical proof-of-concept (POC) has been achieved with several antibodies and small molecules targeted against tyrosine kinases. With Herceptin, Glivec and Iressa (registered in Japan), the first kinase drugs have entered the market. This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Kit, Fms-like tyrosine kinase [Flt]-3), briefly describes new targets, and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors.     

The use of selective pharmacological inhibitors to delineate signal transduction pathways activated during complement receptor-mediated degranulation in chicken heterophils

Complement receptors (CRs), along with Fc receptors, play a primary role in the removal of bacterial pathogens in poultry. The binding of serum-opsonized bacteria to CR results in the secretion of both toxic oxygen metabolites and antibacterial granules. We have previously shown that the stimulation of chicken heterophils with serum-opsonized Salmonella enteritidis induced tyrosine kinase-dependent phosphorylation regulated degranulation. In the present studies, we used selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipases C and D (PLC and PLD), phosphatidylinositol 3'-kinase (PI3-K), and the super family of mitogen-activated protein kinases (MAPKs) on CR-mediated heterophil degranulation. Inhibitors of receptor-linked tyrosine kinases (the tryphostins AG1478 and AG1296) had no attenuating effects on CR-mediated degranulation. However, PP2, a selective inhibitor of the src family of protein tyrosine kinases, and piceatannol, an inhibitor of Syk tyrosine kinases, both significantly attenuated the CR-mediated degranulation. Additionally, the specific inhibitors of PLC, U73122, and PI3-K, LY294002, significantly decreased CR-mediated heterophil degranulation. Two inhibitors of PLD-mediated signaling, 2,3-diphosphoglycerate (2,3-DPG) and 1-butanol, hindered degranulation. Addition of purified PLD restored control levels of degranulation in heterophils in which PLD was inhibited. Lastly, SP600125, a selective inhibitor of c-Jun N-terminal kinase (JNK), inhibited degranulation; whereas neither PD98059, the inhibitor of p38 MAPK, nor SB203580, the inhibitor of extracellular signal-regulated kinase, had any effect on CR-mediated heterophil degranulation. These studies demonstrate that CRs on chicken heterophils lack intrinsic tyrosine kinase activity, but that binding of serum-opsonized bacteria activates both proximal tyrosine kinases (src and Syk kinases), but differentially activates downstream tyrosine kinases (JNK, but not p38 nor ERK). Activation of src and Syk kinases plays a significant role in signal transduction of heterophil degranulation probably by stimulating downstream phosphorylation of PLC, PLD, and PI3-K. PI3-K has also been recently shown to be an upstream mediator of JNK activation, suggesting that this enzyme can induce signaling as both a lipid kinase and protein kinase. Engaging CRs on chicken heterophils activates a proximal tyrosine kinase (src and Syk kinases)-->PLC (PLD)-->PI3-K-->JNK signal transduction pathway that induces degranulation.