尼罗替尼的合成

5-溴-3-三氟甲基苯胺和4-甲基-1H-咪唑在碳酸铯和碘化亚铜作用下缩合,得到3-三氟甲基-5-(4-甲基-1H-咪唑-1-基)苯胺(4).另用3-氨基-4-甲基苯甲酸乙酯(5)与氨腈成胍6,6与3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮环合得4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯(8),8经叔丁氧羰摹保护、水解,再与4经酰胺化、脱保护后得到尼罗替尼,总收率40%(以5计).     

针对Abl-T315I突变的Bcr-Abl蛋白激酶抑制剂的研究进展

Bcr-Abl融合基因与慢性粒细胞白血病(CML)的发病发展密切相关.直接作用于Bcr-Abl蛋白的小分子药物是目前治疗CML的重要方法,受到广泛的关注.伊马替尼作为首个上市的Bcr-Abl蛋白激酶抑制剂,在靶向治疗慢性粒细胞白血病上取得了很大成功,但Bcr-Abl基因的突变导致其出现耐药性,尤其以Abl-T315I突变的耐药程度最高.本文综述了近年正在开发中的针对Abl-T315I突变的Bcr-Abl蛋白激酶抑制剂.     

伊马替尼--酪氨酸激酶抑制剂

文章较为全面地论述了伊马替尼用于慢性粒细胞白血病及胃肠道间质性肿瘤的治疗,对其药动学、药效学及药物相互作用进行了完整的评价,并阐述了本品在临床上的应用及未来的研究方向,可为临床应用提供依据,为进一步研究提供参考。     

酪氨酸激酶抑制剂初始治疗慢性粒细胞白血病的研究进展

目的:为慢性粒细胞白血病慢性期(CML-CP)患者的初始治疗提供参考。方法:根据文献,对近年来酪氨酸激酶抑制剂(TKI)伊马替尼(IM)、达沙替尼、尼罗替尼初始治疗CML-CP的研究现状进行综述。结果与结论:CML-CP一线治疗提高IM初始给药剂量(600～800mg.d-1)与IM标准治疗剂量(400mg.d-1)相比未显示明显优势,对于疗效欠佳的患者可在血药浓度监测的基础上个体化给药;达沙替尼(100mg.d-1)或尼罗替尼(每次300mg,每日2次)在初始治疗CML-CP的Ⅲ期临床试验中较IM标准治疗方案显示更优疗效,可能预示更长期生存获益。成人CML-CP一线治疗可采用IM(400mg.d-1)、达沙替尼(100mg.d-1)或尼罗替尼(每次300mg,每日2次)方案,长期治疗可耐受。     

伊马替尼耐药慢性粒细胞白血病治疗进展

异基因造血干细胞移植目前尚不能在临床广泛应用.在过去的25年间,肿瘤治疗领域最具代表性的进展之一即为伊马替尼成为临床广泛使用的CML一线治疗药物.对伊马替尼耐药的CML者可考虑选择达沙替尼、高剂量伊马替尼、异基因造血干细胞移植、干扰素以及第二代酪氨酸激酶(ABL)抑制剂的联合治疗.     

小分子EGFR酪氨酸激酶抑制剂盐酸埃罗替尼

盐酸埃罗替尼是一种小分子表皮生长因子酪氨酸激酶可逆抑制剂,通过抑制酪氨酸激酶的磷酸化,阻断信号传导,抑制肿瘤生长.临床前研究表明其对表皮生长因子酪氨酸激酶有抑制作用;临床研究显示该药对多种肿瘤有抗肿瘤活性,不良反应较轻,与化疗药物合用不增加毒性.2004年经FDA批准上市,用于一线化疗失败的局部晚期或转移性非小细胞肺癌的治疗.     

伯舒替尼的药理研究及临床评价

慢性髓性白血病是一造血系统疾病,与融合基因Bcr-Abl相关,尽管采用酪氨酸激酶抑制剂伊马替尼治疗取得了显著疗效,但部分患者出现耐药或不能耐受。伯舒替尼为Src和Abl激酶的双重抑制剂,主要用于治疗对伊马替尼耐药或不能耐受的慢性髓性白血病,对一些实体瘤也有效。本文综述了其药理作用、药动学、药物相互作用、临床评价及不良反应等。     

伊马替尼的药理作用与临床应用

<正> 慢性骨髓样白血病(CML)大约占所有类型白血病的20％,通过检测有无费城染色体(Ph~+得以诊断。9号和22号染色体长臂相互交换、移位导致正常位于9号染色体上Abelson原癌基因(ABL)和22号染色体上断裂区(BCR)合并,生成异常蛋白酪氨酸激酶(BCR-ABL),它可引起白细胞无法控制的增殖并且凋亡减少。骨髓移植和α-干扰素(IFNα)是常规的治疗手段,然而许多患者对IFNα治疗无效或不能耐受,并且对加速期和危象期CML没有常规的治疗方案。     

伊马替尼耐药慢性粒细胞白血病的药物治疗

伊马替尼(imatinib)是一种酪氨酸激酶抑制剂。通过占据BCR-ABL融合蛋白的ATP结合位点抑制BCR-ABL蛋白的自身磷酸化和底物磷酸化,使BCR-ABL阳性细胞的增生受抑制或者凋亡。伊马替尼是治疗CML的临床一线用药,随着其耐药的出现,不断研发的新药是CML患者新的希望。     

第二代Bcr/Abl酪氨酸激酶抑制剂巴氟替尼

酪氨酸激酶抑制剂伊马替尼对于断裂点集中区/艾贝尔森(Bcr-Abl)阳性白血病有着显著的治疗效果,但由于抗药性的原因影响了其在临床上的应用。作为第二代Bcr-Abl酪氨酸激酶抑制剂巴氟替尼在一系列临床前和临床后研究中表现出了良好的应用前景。     

Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia

To prevent the resistance to Glivec in patients with chronic myelogenous leukaemia (CML), it is necessary to get a good understanding of its potential mechanisms. The present hypothesis accents on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by Glivec, but alternative signalling pathways become activated-the potential reason associates with activation of telomerase after long-term treatment with Glivec and recovery of cell proliferation and immortality. The hypothesis is based on the observations about differences in telomere dynamics and telomerase activity between chronic and blast phases of CML patients, as well as about the potential effect of Glivec on the cross-talk between telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes in CML. It proceeds from recently published data, demonstrating that protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase. During optimization of chemical structure, Glivec loose its effect on protein kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a high potential to activate telomerase indirectly through its effect on both kinases. Experimental preclinical data are given in confirmation of this hypothesis.     

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.     

针对T315I突变的Bcr—Abl酪氨酸激酶抑制剂研究进展

BCR-ABL是一种由bcr基因和c-abl原癌基因融合产生的致癌基因。该基因表达的Bcr-Abl癌蛋白是慢性粒细胞白血病的病理学基础。因此研发选择性的Bcr-Abl酪氨酸激酶抑制剂成为治疗慢性粒细胞白血病的一种有效策略。目前已有数个Bcr-Abl酪氨酸激酶抑制剂获准上市。然而,Abl激酶结构域的突变或其他原因导致肿瘤耐药性的出现,其中T315I突变是最重要的突变之一,引发的耐药性更是难以克服。重点介绍了针对T325I突变的Bcr-Abl酪氨酸激酶抑制剂的研究进展。     

酪氨酸激酶抑制剂帕唑帕尼的药理与临床研究

帕唑帕尼为一种新型多靶点酪氨酸激酶抑制剂,临床用于治疗肾细胞癌。该药在临床前和临床研究中表现出了较强的抗肿瘤活性,且耐受性较好。文中通过文献检索对该药的药理作用、药动学、临床研究及安全性等进行了综述。     

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.     

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。     

The expanding role of nilotinib in chronic myeloid leukemia

Importance of the field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.

Areas covered in this review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed.

What the reader will gain: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making.

Take home message: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents.     

Rociletinib,a third generation EGFR tyrosine kinase inhibitor: current data and future directions

Introduction: Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms.

Areas Covered: EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression on rociletinib, and future directions.

Expert Opinion: It is important to note that there are other 3^rd generation EGFR TKIs with activity against T790M already approved by the US FDA (osimertinib) and many others in development. Future research will focus on figuring out which patients can benefit the most from a particular medication with minimal side effects, and further resistance mechanisms after rociletinib.     

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.