多激酶抑制药索拉非尼

索拉非尼是首个口服多激酶抑制药,靶向作用于肿瘤细胞和肿瘤血管上的丝氨酸和（或）苏氨酸及受体酪氨酸激酶,阻断信号传导,抑制肿瘤生长。临床前研究显示,索拉非尼作用的2种激酶会影响肿瘤细胞增生及血管生成,而此2种行为为肿瘤生长时所不可或缺。2005年底经FDA批准上市,用于进展性肾脏细胞恶性肿瘤的治疗。本文对索拉非尼的药理学、药动学以及临床应用等方面的研究成果进行综述。     

新型肿瘤治疗药物--酪氨酸激酶抑制剂

酪氨酸激酶介导的信号转导与肿瘤发生发展直接相关,针对这一途径研发药物已成为当前抗肿瘤治疗的热点,并且取得了重要进展.该文综述酪氨酸激酶的作用机制、酪氨酸激酶抑制剂的临床应用现状及其存在的问题.     

小分子酪氨酸激酶抑制剂研究进展

目的:探讨小分子酪氨酸激酶抑制剂(TKI)的作用机制、临床应用与个体化给药。方法:查阅国内、外文献,归纳目前小分子TKI的作用特点及临床应用。结果与结论:酪氨酸激酶(TK)与细胞的增殖、分化、迁移和凋亡有着密切的关系,在细胞生命活动的信号转导途径中扮演着十分关键的角色。小分子TKI已成为当前国际抗肿瘤药研究的热点,其临床应用及个体化给药已取得重要进展。     

FLT-3受体酪氨酸激酶抑制剂的研究进展

FMS样酪氨酸激酶3 (FLT-3)是Ⅲ型受体酪氨酸激酶的一种,广泛存在于血液系统、免疫系统和神经系统中。FLT-3基因突变（内部串联重复突变和激酶区的点突变）以及过度表达将会导致肿瘤的发生,小分子FLT-3受体酪氨酸激酶抑制剂通过阻断细胞增殖信号的传导促使肿瘤细胞凋亡,从而对肿瘤疾病进行治疗。文中对近年来已上市或处于临床研究阶段的小分子FLT-3受体酪氨酸激酶抑制剂按结构分成芳香脲、嘧啶胺、吲哚并咔唑及其他共4类,并简要介绍其代表化合物的药效及临床研究进展。     

酪氨酸激酶靶标治疗肝细胞肝癌的研究进展

肝细胞肝癌是肝细胞原发性恶性肿瘤,具有发现晚、死亡率高等特点。分子靶向药物如酪氨酸激酶抑制剂极有希望成为肝癌治疗药物,目前已引起特别关注,研究者已对酪氨酸激酶受体抑制剂进行了深入研究。本文对多种酪氨酸激酶受体作用于肝癌细胞的机制以及肿瘤细胞内在和外在的抵消激酶抑制剂作用的机制进行了讨论,同时对目前多靶标激酶抑制剂抗肝癌药物的优越性和可行性及其临床研究进展进行综述和展望。     

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。     

5,8-二取代喹唑啉类化合物LJK-11对HER2高表达肿瘤细胞的作用和分子机制初探

目的观察LJK-11对HER2高表达细胞的作用。方法检测LJK-11对不同肿瘤细胞作用的剂量效应;用Western blot检测药物引起的细胞内酪氨酸激酶信号表达变化。结果随着药物浓度的增加,LJK-11对肿瘤细胞的增殖抑制作用逐渐明显,并能够引起肿瘤细胞的凋亡;Western blot检测显示受体酪氨酸激酶HER2磷酸化表达降低。结论LJK-11可能是一种新型的酪氨酸激酶抑制剂,这一作用机制将为研制出新型的抗肿瘤药提供理论依据。     

抗肿瘤新靶点黏着斑激酶FAK及其抑制剂研究进展

FAK是细胞内一种非受体酪氨酸激酶,参与胞内多条信号通路的传导。FAK在多种类型的肿瘤细胞中都出现表达量和活性上调现象,通过激酶依赖和非激酶依赖机制参与肿瘤细胞侵袭、转移、增殖、生长和抗凋亡等多个过程,是目前研究较多的抗肿瘤靶点之一。多个不同机制的FAK抑制剂正处于临床前研究和临床试验阶段,能够抑制特定类型肿瘤的生长、转移等。本文对近年来FAK与肿瘤的关系以及FAK抑制剂抗肿瘤作用的研究进展进行综述。     

分子靶向的小分子抗肿瘤药物的临床合理应用

目的:为分子靶向的小分子抗肿瘤药物临床合理应用提供更多更好的选择。方法:全面综述近些年应用于临床的靶向酪氨酸激酶的小分子抗肿瘤药物。结果与结论:分子靶向的小分子抗肿瘤药物与一般的细胞毒药物不同,它有特异的靶点,针对性更强,有效率更高,不良反应更少,但个体差异比较明显。选择性作用于酪氨酸激酶的小分子抗肿瘤药物研发已成为抗肿瘤药物研发的热点。     

靶向酪氨酸激酶治疗癌症

抑制病理酪氨酸激酶作用的分子靶向药物应用于临床,是近年来癌症研究领域里最令人振奋的进展之一。过去10年的临床研究已证实酪氨酸激酶抑制剂对癌症患者安全有效,其中的一些已成为特定类型肿瘤的标准治疗药物,例如针对BCR-ABL和其他激酶的伊马替尼(imatinib)、针对HER2/ErB2受     

PROTEIN TYROSINE KINASE ACTIVATION BY POLYCYCLIC AROMATIC HYDROCARBONS IN HUMAN HPB-ALL T CELLS

It has been well established that certain polycyclic aromatic hydrocarbons (PAHs), such as 7,12-dimethylbenz\[a]anthracene (DMBA), 3-methylcholanthrene (3MC), and benzo\[a]pyrene (BaP), produce immunotoxicity and cancer in rodents and that these effects are also likely seen in humans. Our laboratory has found that polycyclic aromatic hydrocarbons (PAHs) produce an increase in intracellular Ca2+ in lymphocytes that appears to correlate with their immunotoxicity. Specifically, immunotoxic PAHs, such as DMBA and BaP, have been shown to produce a sustained increase in intracellular Ca2+ in lymphocytes, whereas nonimmunosuppressive PAHs, such as benzo\[e]pyrene (BeP) and anthracene, do not. Our studies previously demonstrated that the rapid increase in intracellular Ca2+ produced by DMBA in HPB-ALL T cells was caused by protein tyrosine kinase (PTK) activation in human T cells, leading to tyrosine phosphorylation of phospholipase C (PLC) and IP-dependent Ca2+ mobilization. However, the specificity of PTK activa1 3 tion by PAHs was not established. In the present studies, we extend our observations of PTK activation by examining a number of PAHs for their effects on total and specific (Fyn and ZAP-70) PTK activity. We show that 10 mu M concentrations of PAHs nonspecifically and rapidly (within 5 min) stimulate PTKs in the HPB-ALL human T cell line. BeP and anthracene were found to be nearly as effective at increasing total tyrosine kinase activity as DMBA, 3MC, and BaP, observed 5 min after exposure. We found that only immunotoxic PAHs activated the Fyn and ZAP-70 PTKs at 10 min, but total PTK activity was still increased by nonimmunotoxic PAHs, BeP, or anthracene after 10 min of exposure. These studies demonstrate that immunotoxic PAHs increase total and specific PTK activity in the human HPB-ALL T cell line. Thus the rapid increase in PTK activity produced by PAHs may not correlate with the immunotoxicity of these agents.     

Protein tyrosine kinase activation by polycyclic aromatic hydrocarbons in human HPB-ALL T cells

It has been well established that certain polycyclic aromatic hydrocarbons (PAHs), such as 7,12-dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (3MC), and benzo[a]pyrene (BaP), produce immunotoxicity and cancer in rodents and that these effects are also likely seen in humans. Our laboratory has found that polycyclic aromatic hydrocarbons (PAHs) produce an increase in intracellular Ca2+ in lymphocytes that appears to correlate with their immunotoxicity. Specifically, immunotoxic PAHs, such as DMBA and BaP, have been shown to produce a sustained increase in intracellular Ca2+ in lymphocytes, whereas nonimmunosuppressive PAHs, such as benzo[e]pyrene (BeP) and anthracene, do not. Our studies previously demonstrated that the rapid increase in intracellular Ca2+ produced by DMBA in HPB-ALL T cells was caused by protein tyrosine kinase (PTK) activation in human T cells, leading to tyrosine phosphorylation of phospholipase C (PLCgamma) and IP3-dependent Ca2+ mobilization. However, the specificity of PTK activation by PAHs was not established. In the present studies, we extend our observations of PTK activation by examining a number of PAHs for their effects on total and specific (Fyn and ZAP-70) PTK activity. We show that 10 microM concentrations of PAHs nonspecifically and rapidly (within 5 min) stimulate PTKs in the HPB-ALL human T cell line. BeP and anthracene were found to be nearly as effective at increasing total tyrosine kinase activity as DMBA, 3MC, and BaP, observed 5 min after exposure. We found that only immunotoxic PAHs activated the Fyn and ZAP-70 PTKs at 10 min, but total PTK activity was still increased by nonimmunotoxic PAHs, BeP, or anthracene after 10 min of exposure. These studies demonstrate that immunotoxic PAHs increase total and specific PTK activity in the human HPB-ALL T cell line. Thus the rapid increase in PTK activity produced by PAHs may not correlate with the immunotoxicity of these agents.     

Inhibitors of tyrosine kinases in the treatment of psoriasis

Psoriasis is a heterogenous skin disease, characterized by epidermal hyperproliferation, abnormal keratinization and inflammation. The heterogeneity of the disease results probably from the interaction of multiple gene abnormalities with environmental factors. The new approaches to drug design have become refocused to the emerging understanding of the role of signaling pathways in health and disease. Protein tyrosine kinases (PTKs) regulate cell proliferation, differentiation and immune processes. Uncontrolled signaling from receptor and intracellular tyrosine kinases can lead to numerous proliferative diseases: cancer, leukemia, restenosis and psoriasis. Identification of PTKs that play a key role in a defined disease can lead to a selective drug. The balance of signals which regulate the homeostasis of normal epidermis is altered in psoriasis. Several lines of evidence suggest a role for the EGF receptor system in this process. Therefore, blockers of the EGFR kinase were suggested as potent antipsoriasis agents. PTK inhibitors from the tyrphostin family were found to block EGF - dependent cell proliferation. AG 1571 (SU 5271) potently inhibits ligand-induced autophosphorylation of EGF-R, downstream signal transduction events, DNA replication and cell cycle progression at micromolar concentrations, as well as proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. AG 1571 (SU 5271) has been in clinical trials by SUGEN Inc. since early 1997. Overexpression of the EGFR is the hallmark of most epithelial cancers. Therefore one can view blockers of the EGFR kinase as becoming universal inhibitors. Tyrphostins are the first signal transduction agents to be used in the clinic. This article summarizes recent progress in the development of PTK inhibitors in the treatment of psoriasis.     

Evidence for a role of protein tyrosine kinases in cell death induced by gp120 in CHP100 neuroblastoma cells

HIV-1 coat protein gp120 is able to kill neuronal cells in culture. Here we address the possible role of protein tyrosine kinases (PTKs) in gp120-induced neurotoxicity using the CHP100 human neuroblastoma cell line as experimental model. For this purpose, the effect of specific PTK inhibitors like genistein, herbimycin A and lavendustin A was evaluated on CHP100 cell death elicited by the viral protein. Here we report that genistein (1-10 microM) significantly reduced the cytotoxic effects induced by gp120 (10 pM). The same protective action was offered by a pre-treatment with herbimycin A (0.1-1 microM) or lavendustin A (1-10 microM). Conversely, daidzein (1-100 microM), a genistein analogue devoid of PTK inhibitory properties, failed to reduce CHP100 cell death caused by gp120. These findings suggest that PTKs can be involved in the signal transduction cascade by which the glycoprotein induces neurotoxicity.     

A shikonin derivative, beta-hydroxyisovalerylshikonin, is an ATP-non-competitive inhibitor of protein tyrosine kinases

Studies of the mechanism of action of a shikonin derivative, beta-hydroxyisovalerylshikonin (beta-HIVS), have revealed that beta-HIVS inhibits the protein tyrosine kinase (PTK) activities of the receptor for epidermal growth factor and v-Src. In this review, we compare the characteristics of the inhibition of PTK activity by beta-HIVS with those of other inhibitors of PTKs. The chemical structure of beta-HIVS is completely different from that of ATP and it does not resemble any of the PTK inhibitors reported to date, except that it includes the benzylidene moiety. In contrast to most PTK inhibitors, the mechanism of inhibition by beta-HIVS is non-competitive with respect to ATP, but competitive with respect to its peptide substrate. This feature of the mechanism of inhibition of PTK by beta-HIVS suggests that it might be useful in a clinical setting with other PTK inhibitors. When Bcr-Abl-positive, human leukemia K562 cells were treated simultaneously with beta-HIVS and STI571 (Gleevec), these compounds had a synergistic effect on both the induction of apoptosis in K562 cells and the inhibition of the phosphorylation activity of PTK, probably because the mechanism of interference with phosphorylation by beta-HIVS and the binding site of beta-HIVS are different from those of STI571.     

Protein tyrosine phosphatases, new targets for cancer therapy

Cellular growth and development are regulated by reversible phosphorylation of tyrosine residues in target proteins. Protein tyrosine phosphatases (PTPs) catalyse removal, and protein tyrosine kinases (PTKs) the addition of phosphate. Data from various sources support a role for PTKs in transformation and it has long been hypothesized that some PTPs will function as tumour suppressor genes. Specific PTPs are down-regulated in some tumours, sometimes in association with ectopic expression of PTKs. Alternatively, other PTPs dephosphorylate and activate PTKs, and are themselves oncogenic. Much current interest surrounds the clinical introduction of specific PTK inhibitors, whereas targeting of PTPs remains largely unexplored. Phosphatases represent 4% of the drugable human genome and PTPs appear an important new target for cancer therapy. Here we briefly, describe PTP structure and function. Secondly, we review experimental and clinical data, which support a role for PTPs in neoplastic development. Next, we review current strategies for generation of agents targeting PTPs; these include re-expression of tumour suppressor genes (mediated via adenoviral vectors), and generation of small molecules designed to inhibit oncogenic activity. Finally, we address the role of PTPs in melanoma, an increasingly common tumour that may represent an appropriate target for therapeutic manipulation of PTP activity.     

Genistein directly inhibits native and recombinant NMDA receptors

The protein tyrosine kinase (PTK) inhibitor genistein has been widely used to examine potential effects of tyrosine phosphorylation on neurotransmitter function. We report here that genistein inhibits N-methyl-d-aspartate (NMDA) receptors through a direct effect. Whole-cell NMDA-activated current was recorded in native receptors from mouse hippocampal slice culture and rat recombinant NR1aNR2A and NR1aNR2B receptors transiently expressed in HEK293 cells. Extracellular application of genistein and NMDA reversibly inhibited NMDA-activated current. The inhibition of NMDA-activated current by genistein applied externally was not affected when genistein was also pre-equilibrated in the intracellular solution. Daidzein, an analog of genistein that does not block PTK, also inhibited NMDA-activated current. Coapplication of lavendustin A, a specific inhibitor of PTK, had no effect on the NMDA response. Moreover, genistein-induced inhibition of NMDA-activated current displayed concentration- and voltage-dependence. Our results demonstrate that genistein has a direct inhibitory effect on NMDA receptors that is not mediated via inhibition of tyrosine kinase. Thus, other PTK inhibitors may be more suitable for studying involvement of PTKs in NMDA receptor-mediated events.     

Conformationally constrained peptides as protein tyrosine kinase inhibitors

Protein kinases are enzymes that catalyze the transfer of the γ-phosphate group from ATP to the hydroxyl groups in side chains of tyrosine, serine, or threonine. Protein kinases are divided in two classes: tyrosine kinases (TKs) and serine/threonine kinases (STKs). Overexpression or activation of protein tyrosine kinases (PTKs) has been found to be responsible for the development of many diseases, including cancer, inflammation, and many cardiovascular and neurodegenerative disorders. Thus, the design of PTK inhibitors (PTKIs) has become a subject of a major interest for the pharmaceutical industry. A number of marketed PTKIs that target conserved ATP binding site of PTKs were found to demonstrate toxicity (e.g., imitanib and sorafenib) or to generate resistance (e.g., imitanib and vemurafenib in chronic myeloid leukemia and metastatic melanoma, respectively). Thus, alternative strategies are urgently required for designing novel PTKIs. Linear peptides designed based on the natural protein substrates of PTKs have been introduced to target unique and non conserved PTK regions, such as substrate binding site. These compounds are more specific than the small molecules that usually target conserved ATP binding site. On the other hand, linear peptides are susceptible to hydrolysis by endogenous peptidases. Cyclization of linear peptides has led to generation of diverse conformationally constrained structures as PTKIs. Introduction of the conformational constraints enhances the stability towards proteases, the free energy upon binding, and binding affinity, but reduces the conformational entropy penalty upon receptor binding. Herein, design strategies for conformationally constrained peptides and their application as PTKIs are discussed.     

Protein tyrosine kinase inhibitors: new treatment modalities?

Protein tyrosine kinases (PTKs) have been recognized as attractive cell-signaling targets for drug discovery in the treatment of cancer and other diseases. Most of the PTK inhibitors are small molecules, designed to compete for, or nearby, the ATP-binding site, and are currently in phase I-III clinical trials, mainly for oncological indications. Recent efforts focused on the synthesis of selective PTK inhibitors have generated several promising clinical candidates, which recently culminated in the approval of Gleevec, the first kinase inhibitor registered for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors.     

High-throughput methods in identification of protein tyrosine phosphatase inhibitors and activators

Reversible protein tyrosine phosphorylation, catalysed by the counter-actors protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a fundamentally important regulatory mechanism of proteins in living cells, controlling cell communication, proliferation, differentiation, motility, and molecular trafficking. The activities of PTPs and PTKs are derailed in several diseases such as cancer and type II diabetes, making them attractive drug targets. Developing drugs against PTKs has started a decade earlier than that on PTPs, and at present there are several molecules targeting PTKs on the market. PTPs in turn are of raising interest, with PTP1B on the lead for its effects on type II diabetes and obesity. In the search for modulators of PTP activity, high-throughput methods are important as the initial step to find suitable lead compounds for drug development. Also, high-throughput methods are very useful in elucidating the specific function of different PTPs. In this review, the different high-throughput studies performed to find inhibitors and activators of classical PTPs are discussed.