含3-羟基-4-吡啶酮片段的EGFR酪氨酸激酶抑制剂的合成及抗肿瘤活性研究

目的设计合成含具备铁离子螯合功能的3-羟基-4-吡啶酮片段的4-芳胺基喹唑啉类衍生物,并评价其体外抑制肿瘤增殖活性。方法 4-芳胺基-6-硝基-7-氟喹唑啉与3-苄氧基吡啶-4-酮脂肪醇发生取代反应,再经过硝基还原得到4-芳胺基-6-氨基-7-(3-苄氧基-4-吡啶酮)烷氧基喹唑啉中间体,该中间体与各种酰氯或者酸缩合后再脱去苄基得到目标化合物1~6;4-芳胺基-6-氨基-7-烷氧基喹唑啉与3-苄氧基吡啶-4-酮-1-乙酸经缩合后脱苄基得到目标化合物7~12。采用MTT法,以吉非替尼(gefitinib)为阳性对照药,测定目标化合物对人表皮癌细胞系A431、人肺腺癌细胞系H1975和人宫颈癌细胞系HeLa的增殖抑制活性。结果与结论合成了12个未见文献报道的新化合物,其结构经~1H-NM R、MS谱确证;初步体外生物活性筛选结果显示,该类化合物具有较好的抗肿瘤细胞增殖活性,其中化合物1~4、7~10在人表皮癌A431细胞株上的抗增殖活性与阳性对照吉非替尼相当。     

VEGF受体酪氨酸激酶抑制剂的研究进展

肿瘤的生长和侵袭、转移依赖于新生血管的形成.抑制肿瘤介导的血管生成,阻断癌细胞的营养途径,就可有效抑制癌细胞增殖.血管内皮生长因子(VEGF)是肿瘤新生血管形成中的关键性促血管生长因子,它与特异性高表达在新生血管内皮细胞表面的受体酪氨酸激酶结合,激活酪氨酸激酶从而发挥生物学功能.因而以VEGF受体酪氨酸激酶为靶点的肿瘤血管靶向性治疗已成为近几年肿瘤治疗的新途径[1-3].     

蛋白酪氨酸激酶抑制剂的进展与临床评价

目的：归结于药学和生物工程技术的进步,把对肿瘤细胞的攻击锁定于表皮生长因子和血管内皮生长因子等靶位,使药物治疗的切入点由细胞水平向分子水平过度,提高肿瘤联合治疗的效果,成为肿瘤综合治疗策略。由此应运而生蛋白酪氨酸激酶抑制剂独树一帜,对其研究和评价日趋活跃,本文总结其作用优势和临床评价。方法：采用国内、外文献综述方法。结果及结论：酪氨酸激酶抑制剂疗效确切、特异性强、不良反应和耐药性小,无疑是药学研究领域中的巨大突破。     

多重靶向的4-取代苯胺喹唑啉类衍生物抗肿瘤活性研究进展

4-取代苯胺喹唑啉类化合物是喹唑啉类酪氨酸激酶抑制剂中活性较高的一类化合物,其对表皮生长因子受体、血管内皮生长因子受体、组蛋白去乙酰化酶等均有抑制作用,已成为抗肿瘤药物的研究热点。综述了近几年多重靶向的4-取代苯胺喹唑啉类化合物抗肿瘤活性的研究进展。     

血管内皮细胞生长因子受体酪氨酸激酶抑制剂

血管生成是人体肿瘤生长和转移的必要条件，抑制肿瘤细胞介导的血管生成已成为近年来寻找新型抗肿瘤药物的一个主要研究方向，血管内皮细胞生长因子（VEGF）是体内活性最强，专属性最高的促血管生成因子，故成为寻找血管生成抑制剂的重要靶点，其中靶向VEGF受体酪氨酸激酶的抑制剂令人最为关注，本文综述VEGF及其受体酪氨酸酶抑制剂的研究进展，探讨了各类抑制剂的构效关系。     

小分子酪氨酸激酶抑制剂临床研究进展

蛋白酪氨酸激酶（PTK）是一组酶系,分受体型和非受体型。常见的受体型包括表皮生长因子受体（EGFR）家族、胰岛素受体家族、血小板衍化生长因子受体（PDGFR）家族、血管内皮生长因子受体（VEGFR）家族、纤维细胞生长因子受体（FGFR）家族等;非受体型包括SRC、ABL、JAK、ACK、CSK、FAK、FES、FRK、TEC、SYK家族等。PTK是多种肿瘤最常见的生长因子受体,抑制其活性可破坏肿瘤细胞的信号传导,抑制肿瘤细胞增殖和新生血管形成,而对正常细胞影响较小。以PTK为靶点的单克隆抗体,     

喹唑啉结构的多靶点酪氨酸激酶抑制剂研究进展

随着肿瘤机制和抗肿瘤药物的深入认识,多靶点酪鼠酸激酶抑制剂的抗肿瘤作用是临床研究的主要方向,本文对含喹唑啉结构的酪氨酸激酶抑制剂的研究进展作一综述。     

小分子表皮生长因子受体酪氨酸激酶抑制剂的研究进展

表皮生长因子受体是一种具有酪氨酸激酶活性的膜受体,在细胞的增殖、迁移、代谢、分化和存活中发挥重要作用。目前,表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs）的开发已成为肿瘤治疗领域的热点。EGFR-TKIs 分为可逆性EGFR-TKIs 和不可逆性EGFR-TKIs,可逆性EGFR-TKIs 主要包括吉非替尼和厄洛替尼等已上市的药物,不可逆性EGFR-TKIs主要包括阿法替尼和一些正处于临床研究中的药物,如AZD9291、CO-1686 和HM61713 等。本文对EGFRTKIs的研究进展进行了综述,为非小细胞肺癌临床治疗的药物选择提供参考。     

新型喹唑啉类衍生物的合成与抗肿瘤活性的研究

目的 合成一类新型的喹唑啉类衍生物并研究其体外抗肿瘤活性.方法 以2-氨基-5-硝基苯甲腈为起始原料,经过环合、氯化、氨基取代、硝基还原、N-乙酰化等反应得到目标化合物,采用MTT法在前列腺癌细胞PC-3、人卵巢癌细胞SKOV-3、人结直肠癌细胞HCT116、皮肤基底细胞癌细胞A431和人红白血病细胞K562等细胞株上进行了体外抗肿瘤活性测试.结果和结论 合成了3个新型化合物,并经1HNMR、MS确证了化学结构.初步的体外抗肿瘤活性显示化合物具有抗白血病和抗结肠癌活性.     

我院160例酪氨酸激酶抑制剂致不良反应分析

目的：观察酪氨酸激酶抑制剂治疗癌症的不良反应。方法：定期随访服用酪氨酸激酶抑制剂的160例患者,对其服药后的情况进行分析、总结。结果：酪氨酸酶抑制剂引起的不良反应以皮肤系统损害最为常见（占43．88％）,其次是消化系统和呼吸系统。结论：临床上要对使用酪氨酸酶抑制剂的患者加强监测,以免严重不良反应的发生。     

蛋白酪氨酸激酶抑制剂的研究进展

目的综述蛋白酪氨酸激酶(protein tyrosine kinase,PTK)抑制剂类抗肿瘤药物的研究进展。方法根据已报道的PTK抑制剂的相关文献,将其分为国外已经上市、国外处于临床研究和我国自主研发的PTK抑制剂进行具体介绍。结果 PTK在细胞内的信号转导中起着重要的作用,与肿瘤细胞的生长、增殖、分化和凋亡密切相关,目前已经有多种结构的PTK抑制剂类抗肿瘤药物上市或进入临床研究。结论随着PTK的作用机制及构效关系研究的不断深入,该类药物终将成为治疗肿瘤的有效药物。     

Design, synthesis, and in vitro antitumor activity evaluation of novel 4-pyrrylamino quinazoline derivatives

Here, we describe the design and synthesis of two series of 4-pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI-6, GII-4, GII-6, GII-8, and GII-9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure-activity relationship to provide information for designing and developing more potent antitumor agents.     

吉非替尼的合成工艺改进

以3,4-二甲氧基苯甲酸为原料,经硝化、脱甲基、还原、环合、乙酰化、氯化、缩合、水解等反应,最后经过一步与N-（3-氯丙基）吗啉缩合得到抗肿瘤药吉非替尼。     

Dacomitinib: an investigational drug for the treatment of glioblastoma

ABSTRACT

Introduction: Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only 15 months. It seems imperative to explore new possibilities of treatment based on targetable alterations known to be present in GB. Among others, Epidermal Growth Factor Receptor or EGFR (HER1) mutations or amplifications are the most prevalent alterations in GB. In fact, around 40% of GB cases show amplification of EGFR gene, and half of these patients carry the EGFRvIII mutation, a deletion that generates a continuous activation of the tyrosine kinase domain of the receptor.

Areas covered: We review the current knowledge about Dacomitinib, an oral, irreversible, second-generation, pan-HER tyrosine kinase inhibitor, in the treatment of glioblastoma. Dacomitinib has noteworthy antiglioma activity in preclinical models and has been tested in one phase II trial in patients with recurrent GB with EGFR amplification.

Expert opinion: Despite the poor global results of Dacomitinib in recurrent GB shown in a phase II trial, some patients had a significant benefit. Therefore, it is necessary to improve the knowledge about the mechanisms of failure or resistance to EGFR inhibitors in GB.     

Antitumor activity of a novel EGFR tyrosine kinase inhibitor against human lung carcinoma in vitro and in vivo

Summary  Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with non-small cell lung cancer (NSCLC). However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the antitumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor (Zhao260054). In vitro studies in a panel of four different human lung cancer cell lines revealed that Zhao260054 inhibited cell proliferation with high potency and induced G₀/G₁ arrest of cell cycle and apoptosis. Zhao260054 markedly reduced phosphorylation of EGFR and inhibited activation of ERK1/2 and AKT. Oral administration of Zhao260054 (200 mg/kg/day) to BALB/c nude mice bearing SPC-A1 xenografts significantly retarded tumor growth. In conclusion, Zhao260054 has potent antitumor activity on human lung cancer in vitro and in vivo.     

Emerging drugs for EGFR-mutated non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity.

Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance.

Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL).

Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 – 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL.

Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups.

Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.     

血管内皮生长因子受体酪氨酸激酶抑制剂的研究进展

血管生成在肿瘤的生长、转移和演进中起着非常重要的作用.文中简要阐述了血管内皮生长因子受体(VEGFR)酪氨酸激酶介导的RAS/Raf/MAPK,P13K/AKT,PLC-γ及Src信号转导途径,根据结构类型统计和介绍了已经上市或处于临床研究的VEGFR酪氨酸激酶小分子抑制剂,包括吲哚酮类、喹唑啉类、哒嗪类、吲唑类、烟碱类和吡咯并嘧啶类等典型结构,分别阐述了这几类结构中代表性化合物的临床前研究和临床研究的数据.     

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。