血管生成抑制剂的研究进展

目的探讨血管生成抑制剂的作用靶点及其分类,对临床研究进展进行综述,尤其在肿瘤方面,为新药合成和发现提供参考。方法综述了近年来国内外相关报道,根据血管生成抑制剂的作用靶点进行分类,并对临床研究和作用机制进行讨论,重点强调了小分子酪氨酸激酶(protein-tyrosine kinases,PTK)抑制剂的分类和作用机制。结果血管生成抑制剂分为八大类,分别进行抗肿瘤治疗的讨论,并就其代表药物及开发上市状况进行概述,同时阐明血管生成抑制剂的其他应用。结论血管生成抑制剂与传统的化疗药物抑制肿瘤细胞相比,能够直接抑制血管生成,这将在抗肿瘤转移方面有广阔的前景。     

蛋白酪氨酸激酶抑制剂的研究进展

蛋白酪氨酸激酶（PTK）抑制剂是一类作用于细胞信号转导通路的分子靶向药物,针对特定靶点发挥抗肿瘤作用。目前已有十余种蛋白酪氨酸激酶抑制剂上市,且它们在多种实体瘤的治疗中显示出较好的疗效。该文对近年来蛋白酪氨酸激酶抑制剂的研究进展做简要综述。     

国外研究中的抗肿瘤新药

本文主要介绍国外目前正在临床研究中的抗肿瘤新药,其中少数药物已经上市。下面分为烷化剂、抗代谢药物、植物药、抗生素、杂类药物和免疫药物六类进行介绍(后几类中具有烷化剂和抗代谢作用者,并在前两类中加以介绍)。     

有机硼化合物的药理活性及构效关系研究进展

综述具有药理活性的有机硼化合物及其构效关系的研究进展,包括硼酸类抗肿瘤化合物、含硼杂环类及硼烷类抗感染化合物、硼酸类凝血酶抑制剂以及硼酸类二肽基肽酶抑制剂等。并重点介绍了已上市抗肿瘤药物硼替佐米的药理作用机制、合成方法、药效及临床研究。     

铂类抗肿瘤药物的研发进展及市场情况

近年来,铂类抗肿瘤药物的临床研究进展较快,其抗肿瘤谱广,抗肿瘤活性增强,不良反应降低,已成为目前有关抗肿瘤药物研发的重要领域。新的铂类抗肿瘤药物将从那些在临床研究中显示出低毒性、抗肿瘤谱广、与现有药物无交叉耐药性的化合物中产生。本文就其作用机制、国内外上市开发现状、国内外销售情况及国内研究开发进展等进行综述。     

虎杖中的蛋白酪氨酸激酶抑制剂—大黄素

虎杖的干燥根在中日传统医学中用于治疗化脓性皮肤炎、淋病、黄癣、血脂过多症及脚癣等,从中已经分得的成分有蒽醌、萘醌、芪类和其它酚性化合物,但这些化学研究均未在生物分析指导下对蛋白酪氨酸激酶(PTK)抑制剂进行评价。 PTK为一组在许多必需蛋白中催化磷酯从ATP向羟基酪氨酸转移的酶。这些蛋白在调节细胞生长和转变中起着重要作用。所以PTK也成为调节肿瘤细胞生长的潜在目标。PTK特异性抑制剂的发展可望发现潜在抗肿瘤剂药理并作为药理学探针,解释     

ACEI/ARB类降压药物在肿瘤治疗中的临床研究进展

血管紧张素转化酶抑制剂(ACEI)和血管紧张素受体Ⅱ抑制剂(ARB)类药物是临床心脑血管系统常用药物,一些流行病学研究发现其具有抗肿瘤作用。有一些临床研究表明ACEI/ARB类药物在肿瘤合并高血压人群中表现出潜在的抗肿瘤作用。就其最新临床研究进展进行综述。     

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。     

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。     

针对分子靶点的抗肿瘤药物研究进展

随着肿瘤药理、分子药理学研究的飞速发展，针对分子靶点的抗肿瘤药物研发已成为当今抗肿瘤药物研究开发的重要方向。笔者综述了近年来DNA拓扑异构酶抑制剂、蛋白酪氨酸激酶抑制剂、肿瘤新生血管生成抑制剂、磷脂酰肌醇-3激酶／蛋白激酶B／哺乳动物雷帕霉素靶体（PI3K-AKT-mTOR）信号通路抑制剂、细胞周期依赖性蛋白激酶抑制剂的临床应用和临床研究进展。     

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.     

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。     

Pazopanib: therapeutic developments

Pazopanib (Votrient, GW786034) is a potent pan-VEGF inhibitor in advanced clinical development. Like other orally available VEGFR inhibitors, pazopanib is clinically efficacious and well tolerated. The recently reported Phase III clinical trial in metastatic renal cell carcinoma showed activity similar to approved agents with variations in toxicity which has led to its recent FDA approval. Given the growing number of agents in this category, differences not only in single-agent activity but also toxicity and combinatorial potency will probably distinguish pazopanib from other similar agents.     

多靶点酪氨酸激酶抑制剂舒尼替尼的研究进展

近年来各种酪氨酸激酶抑制剂不断涌现,以酪氨酸激酶抑制剂为代表的分子靶向治疗已成为抗肿瘤研究的热点.舒尼替尼(sunitinib,商品名Sutent)是一种小分子多靶点酪氨酸激酶抑制剂,对血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR)、干细胞因子受体(C-Kit)等多种受体酪氨酸激酶具有抑制作用,已于2006年1月被美国FDA批准用于临床上晚期肾细胞癌(RCC)和对伊马替尼(ima-tinib)耐药和(或)治疗失败的胃肠道间质瘤(GIST)的治疗,并在其他多种肿瘤的临床试验中也显示显著抗肿瘤活性,文中综述了该药的临床前研究及临床研究进展.     

索拉非尼治疗急性髓系白血病的研究进展

作为一种新型多激酶抑制剂,索拉非尼(sorafenib)已被美国FDA批准用于治疗肾细胞癌、肝细胞癌和分化甲状腺癌。而近年来的研究显示通过抑制FMS样酪氨酸激酶-3的活性,该药可发挥一定的抗白血病作用,特别是FMS样酪氨酸激酶-3近膜区的内部串联重复序列(FMS-like tyrosine kinase-3-internal tandem duplication,FLT3-ITD)突变阳性的急性髓系白血病。笔者通过查阅国内外相关文献,对其在治疗急性髓系白血病的药理作用、药物代谢动力学、临床疗效和安全性等方面的研究进展作一综述。     

Bcr-Abl tyrosine kinase inhibitors: a patent review

Introduction: Breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors.

Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compounds that are in clinical trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chemical features.

Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a number of patented compounds could enter clinical trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

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.     

VEGF receptor kinase inhibitors: phthalazines,anthranilamides and related structures

Inhibition of vascular endothelial growth factor receptor (VEGFR) signalling, using either antibodies or small molecule inhibitors of the VEGFR kinase domain, has become a major area of research in oncology. The phthalazine PTK787/ZK222584, first published in the literature in 1998, is one of the most advanced VEGFR inhibitors in the clinic. This paper provides an update on the patenting activity related to the phthalazine class. In addition, newer kinase inhibitor pharmacophores derived from this class (e.g., anthranilamides) will be reviewed.     

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

Introduction: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.

Areas covered: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.

Expert opinion: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.