蛋白酪氨酸激酶抑制剂类抗肿瘤药物的不良反应及疗效性价比

目的：探讨蛋白酪氨酸激酶抑制剂抗肿瘤的不良反应与疗效性价比。方法：回顾性分析2007年1月1日-2008年12月30日的抗肿瘤蛋白酪氨酸激酶抑制剂的不良反应报告。结果：VEGFR引起的不良反应数最好;主要的不良反应的临床表现都是变态反应与消化系统反应;多靶点酪氨酸激酶抑制剂的价值相对较高。结论：蛋白酪氨酸激酶与细胞的增殖、分化、迁移和凋亡有着密切的关系,筛选出合理酪氨酸激酶抑制剂已经成为开发抗肿瘤药物的新途径。     

新型蛋白酪氨酸激酶抑制剂类抗肿瘤药物的研究进展

目的探讨蛋白酪氨酸激酶抑制剂抗肿瘤作用机理及其研究进展。方法综述了最新发现的小分子酪氨酸激酶抑制剂的化学结构、抗肿瘤作用及其作用机制及其发展方向等内容。结果结论蛋白酪氨酸激酶与细胞的增殖、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,筛选酪氨酸激酶抑制剂已经成为开发抗肿瘤药物的新途径。     

酪氨酸激酶抑制剂的研究进展

恶性肿瘤一直严重威胁着人类生命,尽管诊断和治疗水平有所进步,但很多肿瘤生存率一直很低。近年来随着科学的发展,我们对肿瘤的生物学特性有了更深一步的认识。人类蛋白酪氨酸激酶（PTKs）在肿瘤的发生发展过程中起着非常重要的作用．它已成为一种很有前景的肿瘤治疗新靶点。PTKs抑制剂研究已成为当今世界抗肿瘤研究的热点领域,特别是BCR-ABL酪氨酸激酶抑制剂imatinib（STl571）治疗慢性髓细胞白血病的显著成功使得科学家们更热心于投入这一领域的研究．目前,至少有30多种酪氯酸激酶抑制剂在肿瘤治疗的不同临床试验阶段。在此对酪氨酸激酶在肿瘤中的作用及酪氨酸激酶抑制剂在肿瘤治疗中的研究进展作一综述。     

开发中的多靶点酪氨酸激酶抑制剂

多靶点酪氨酸激酶抑制剂是目前抗肿瘤药物研发的热点.相对于单靶点酪氨酸激酶抑制剂,其在疗效及患者耐受性方面都有很大的优势.本文综述蛋白酪氨酸激酶及其与肿瘤的关系,并简要介绍几种开发中的多靶点酪氨酸激酶抑制剂.     

小分子靶向抗癌药物--蛋白酪氨酸激酶抑制剂研究进展

本文综述了一类靶向抗肿瘤药物——蛋白酪氨酸激酶抑制剂的研究进展,并讨论这类药物的靶向抗肿瘤机制。     

槲皮素对PDGF诱导的NIH 3T3细胞增殖的影响

目的研究酪氨酸蛋白激酶抑制剂槲皮素对ＰＤＧＦ诱导的ＮＩＨ３Ｔ３细胞增殖的影响。方法采用ＭＴＴ比色法、Ｇｉｅｍｓａ染色、流式细胞术（测定ＤＮＡ含量的变化及增殖细胞核抗原的表达）、及ＷｅｓｔｅｒｎＢｌｏｔ分析技术对ＰＤＧＦ诱导的ＮＩＨ３Ｔ３细胞增殖进行分析。结果与对照组相比，槲皮素处理可显著地抑制ＰＤＧＦ诱导的ＮＩＨ３Ｔ３细胞增殖，而且主要是细胞周期Ｓ期抑制，ＷｅｓｅｔｅｒｎＢｌｏｔ分析提示槲皮素可明显地抑制ＰＤＧＦ诱导的ＮＩＨ３Ｔ３细胞酪氨酸磷酸化程度。结论酪氨酸蛋白激酶抑制剂可显著地抑制ＰＤＧＦ诱导的ＮＩＨ３Ｔ３细胞增殖，可能是通过抑制酪氨酸蛋白激酶活性来完成。     

酪氨酸蛋白激酶抑制剂的研究进展

酪氨酸蛋白激酶抑制剂的研究进展庞素华，郭宗儒（中国医学科学院，中国协和医科大学药物研究所，北京１０００５０）近年来，酪氨酸蛋白激酶（ｔｙｒｏｓｉｎｅｐｒｏｔｅｉｎｋｉｎａｓｅｓ，简称ＴＰＫ）的研究已引起了广泛兴趣。不少逆转录病毒致癌基因的编码蛋白以及...     

蛋白酪氨酸激酶与糖尿病大鼠主动脉平滑肌高反应性的关系

目的　探讨蛋白酪氨酸激酶在糖尿病大鼠主动脉平滑肌高反应性中的作用。方法　离体主动脉环张力实验。结果　在 8～ 10wk的糖尿病大鼠 :①主动脉平滑肌对苯肾上腺素的浓度依赖性收缩反应显著增加 ,最大收缩反应为( 167± 2 3 ) g·g-1组织净重 ,较对照组 ( 10 0± 17) g·g-1组织净重增加了约 67% ,②蛋白酪氨酸磷酸酶抑制剂sodiumor thovanadate的浓度依赖性收缩反应也明显增强 ,1mmol·L-1sodiumorthovanadate的收缩反应为 ( 2 0 8± 2 5 )g·g-1组织净重 ,较对照组 ( 113± 18) g·g-1组织净重增加了约 85 % ,③蛋白酪氨酸激酶抑制剂 genistein均浓度依赖性地抑制糖尿病组和对照组主动脉平滑肌对苯肾上腺素的收缩反应 ,但在对照组的抑制率显著大于糖尿病组。结论　糖尿病大鼠主动脉平滑肌的高反应性可能与糖尿病时蛋白酪氨酸激酶的活性增加有关。     

不可逆性酪氨酸激酶抑制剂的研究进展

酪氨酸激酶的过度表达和过度激活在许多肿瘤的发生和发展中具有重要意义,因此,多种酪氨酸激酶成为抗肿瘤药物的靶点。目前已经上市的小分子酪氨酸激酶抑制剂多属于可逆性抑制剂,这些药物具有选择性差、药效不够强烈和持久以及易引发耐药性等缺点。近些年,不可逆性酪氨酸激酶抑制剂的研究正方兴未艾。这一类药物分子以不可逆的共价键与酪氨酸激酶上ATP结合域进行结合,从而使该靶点永久性失活。由于其独特的作用机制,不可逆性酪氨酸激酶抑制剂可以有效地解决可逆性酪氨酸激酶抑制剂的几个缺点。目前,已经有一批不可逆性酪氨酸激酶抑制剂进入市场或临床研究阶段。该篇综述是对不可逆性酪氨酸激酶抑制剂的结构、药理和药化特征及其研究进展等进行总结和阐述。     

与2型糖尿病相关的蛋白酪氨酸磷酸酶及其新型降糖药的开发

蛋白酪氨酸磷酸酶作为负性调节胰岛素信号转导的关键酶，对糖尿病的发生、发展有着重要的意义。2型糖尿病和胰岛素抵抗患者体内特异的蛋白酪氨酸磷酸酶含量及活性均有所增加，当蛋白酪氨酸磷酸酶被剔除后，不仅胰岛素敏感性增高，而且糖尿病症状也有所改善。以蛋白酪氨酸磷酸酶作为靶点治疗2型糖尿病显示了其独特的潜力，因此开发蛋白酪氨酸磷酸酶抑制剂和其他以蛋白酪氨酸磷酸酶为靶点的药物具有良好的前景。     

Cardiovascular & Renal: AT2 antagonist inhibition of vascular restenosis

Competition in the field of tyrosine kinase inhibitors has increased in the last few years. New receptor and non-receptor tyrosine kinases have been identified as attractive targets for drug discovery programs. A pharmacophore model of the ATP-binding site of the epidermal growth factor-receptor (EGF-R) tyrosine kinase has been developed and successfully used for the rational design of tyrosine kinase inhibitors. Several inhibitor classes containing a phenylamino-pyrimidine moiety in their structure have provided highly selective ATP-competitive tyrosine kinase inhibitors, active in the low nanomolar or even picomolar range, thus proving that the ATP-binding site of tyrosine kinases is an attractive target for the design of anticancer drugs. More and more examples of inhibitors against several tyrosine kinases are being described which, in addition to showing potent and selective in vitro<> activity, exhibit potency in relevant cellular and in vivo models.<> Presently, several tyrosine kinase inhibitors with an interesting in vitro and in vivo profile are in preclinical evaluation and are expected to enter Phase I clinical trials later this year or early next year. This review summarises development of the last two years in the design and biological profiling of tyrosine kinase inhibitors with special focus on the phenylamino-pyrimidine-containing classes of compounds.     

Forthcoming receptor tyrosine kinase inhibitors

Receptor tyrosine kinases play a significant role in carcinogenesis and have been successfully targeted with monoclonal antibodies and small-molecule inhibitors. There have been recent developments in the understanding of receptor tyrosine kinase signal transduction which have enabled better drug development. The use of receptor tyrosine kinase inhibitors in clinical practice has expanded the knowledge on cancer biology, in particular the understanding of resistant mutations and strategies to overcome such resistance. This has driven drug development from single kinase inhibitors to multi-kinase inhibitors and high-affinity kinase inhibitors. Finally, as the use of receptor tyrosine kinase inhibitors grows in clinical practice, more is learned about appropriate patient selection for such therapies. This is an exciting time in cancer therapeutics, highlighted by the advent of effective targeted therapy with receptor tyrosine kinase inhibitors.     

Forthcoming receptor tyrosine kinase inhibitors

Receptor tyrosine kinases play a significant role in carcinogenesis and have been successfully targeted with monoclonal antibodies and small-molecule inhibitors. There have been recent developments in the understanding of receptor tyrosine kinase signal transduction which have enabled better drug development. The use of receptor tyrosine kinase inhibitors in clinical practice has expanded the knowledge on cancer biology, in particular the understanding of resistant mutations and strategies to overcome such resistance. This has driven drug development from single kinase inhibitors to multi-kinase inhibitors and high-affinity kinase inhibitors. Finally, as the use of receptor tyrosine kinase inhibitors grows in clinical practice, more is learned about appropriate patient selection for such therapies. This is an exciting time in cancer therapeutics, highlighted by the advent of effective targeted therapy with receptor tyrosine kinase inhibitors.     

Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents

Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa? and Tarceva?), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec?). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance.     

Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents

Numerous small molecule synthetic tyrosine kinase inhibitors are in clinical development for the treatment of human cancers. These fall into three broad categories: inhibitors of the epidermal growth factor receptor tyrosine kinase family (e.g., Iressa trade mark and Tarceva trade mark ), inhibitors of the split kinase domain receptor tyrosine kinase subgroup (e.g., PTK787/ZK 222584 and SU11248) and inhibitors of tyrosine kinases from multiple subgroups (e.g., Gleevec trade mark ). In addition, agents targeting other tyrosine kinases implicated in cancer, such as Met, Tie-2 and Src, are in preclinical development. As experience is gained in the clinic, it has become clear that unleashing the full therapeutic potential of tyrosine kinase inhibitors will require patient preselection, better assays to guide dose selection, knowledge of mechanism-based side effects and ways to predict and overcome drug resistance.     

已上市酪氨酸激酶抑制剂抗肿瘤作用机制及构效关系研究

在人类基因组中发现了大约2000个激酶,其中超过90个为蛋白酪氨酸激酶,在靶向性抗肿瘤药物中,靶向酪氨酸激酶类的药物已成为研发热点,并且已获得巨大成功。本文综述了一类已上市的酪氨酸激酶抑制剂的研究进展,介绍了抑制剂结合受体蛋白的方式及其作用机制,重点讨论了这类药物的构效关系,发现分子对接的结构与真实构效关系基本一致。     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

Patent Update: Oncologic,Endocrine & Metabolic Small molecule inhibitors of tyrosine kinase activity

Inhibitors of tyrosine kinases may be effective in the treatment of certain cancers and chronic inflammatory conditions for which current therapy is either inadequate or lacking. As such, tyrosine kinase inhibitors are attractive targets for pharmaceutical research and may emerge as an important new class of therapeutic agents. Significant progress has been made during recent years towards the development of potent and highly selective tyrosine kinase inhibitors. In particular, recent discovery efforts at Zeneca have lead to the identification of very potent and selective inhibitors of EGF receptor tyrosine kinase. Likewise, a class of potent and selective inhibitors of PDGF receptor tyrosine kinase were described by Rhone-Poulenc Rorer and more recently by Ciba-Geigy. New inhibitors of p56^lck and pp60^src were also reported. This review focuses mainly on developments which appeared in the patent literature from 1993 to mid-1995. References to the primary literature are limited to studies which are relevant to the highlighted patents.     

Tyrosine kinase inhibitors, pancreatic hyperenzymemia and acute pancreatitis: a review

The advent of new drugs can rapidly increase the number of substances causing acute pancreatitis. This is the case of tyrosine kinase inhibitors; these drugs are currently used for chronic myeloid leukemia, gastrointestinal stromal tumors, unresectable hepatocellular carcinomas and advanced renal cell carcinomas that and they have been reported to cause acute pancreatitis or asymptomatic elevations of serum pancreatic enzymes. Of the classes of drugs capable of inducing acute pancreatitis, we aimed to evaluate, in which class tyrosine kinase inhibitors can be allocated. A search was carried out using the MEDLINE database in order to select the data existing in the literature on pyrimidines and acute pancreatitis or serum lipase/amylase elevation covering the period from January 1966 to January 2010; thirteen papers were found and utilized for this review. Based on the data in the literature, we found that tyrosine kinase inhibitors may often cause an increase in pancreatic enzymes in plasma and patients treated with these drugs, especially those who are treated with sorafenib, might be at risk of developing acute pancreatitis. Whether acute pancreatitis due to tyrosine kinase inhibitors is associated only with sorafenib or may also be caused by other drugs of the same class remains an open question. Recent patents on tyrosine kinase inhibitors and acute pancreatitis are pointed out in this review.     

Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors

A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 10(2)-10(3) higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.