肿瘤治疗中蛋白酶体抑制剂的临床研究进展

硼替佐米作为第一个蛋白酶体抑制剂已通过美国食品和药物管理局批准应用于临床治疗多发性骨髓瘤并取得较好疗效,越来越多的蛋白酶体抑制剂进入临床研究。本文对现有蛋白酶体抑制剂的临床研究情况进行概述,并对硼替佐米作为第一代抑制剂单独用药和联合用药的临床评价进行综述,最后对蛋白酶体抑制剂的今后发展方向进行了展望,期望能够为今后开发新型蛋白酶体抑制剂提供借鉴。     

新型β-肽环氧酮类蛋白酶体抑制剂的合成与活性评价

目的 设计合成新型的β-肽类蛋白酶体抑制剂,并对其活性进行评价。方法 根据先导化合物Carfilzomib与蛋白酶体的作用方式,保留其与蛋白酶体结合的关键环氧酮片段,并结合β-氨基酸的特点,采用氨基酸替换、生物电子等排等药物设计的方法,设计一类结构新颖的蛋白酶体抑制剂;采用缩合、氧化、还原等反应,合成系列目标化合物;通过体外酶抑制活性实验检验化合物活性。结果 合成了8个结构新颖的β-肽环氧酮类衍生物,化合物结构经1H-NMR、ESI-MS确证,部分化合物体现了一定的蛋白酶体抑制活性。结论 β-氨基酸作为一种重要的α-氨基酸替换结构,有望能够丰富短肽类蛋白酶体抑制剂的结构类型。     

美国FDA批准多发性骨髓瘤治疗药物Carfilzomib上市

美国FDA于2012年7月20日批准美国ONYX PHARMS INC公司产品Carfilzomib(商品名:Kyprolis)注射用冻干粉针剂上市,用于多发性骨髓瘤的治疗,且患者应接受过至少2种疗法(包括硼替佐米和1种免疫调节剂)治疗,并确定有疾病进展,或上次治疗结束60日内。蛋白酶体负责细胞内蛋白质内环境稳定,本药是四肽环氧酮     

Carfilzomib:从天然产物到药物的研发历程

天然产物及其衍生物是药物的重要来源。Carfilzomib是一个以天然产物为先导通过结构优化得到的用于治疗多发性骨髓瘤的药物,其先导化合物Epoxomicin是从微生物中发现的具有抗癌活性的环氧酮肽类天然产物,能够选择性地抑制蛋白酶体,其环氧酮结构以独特的两步反应和蛋白酶体共价结合,因此克服了同类药物的脱靶缺点。以Epoxomicin为先导,通过结构优化得到活性更强、成药性性更好的Carfilzomib,作为新一代蛋白酶体抑制剂于2012年上市。     

首个治疗多发性骨髓瘤的口服药物——依沙佐米

依沙佐米(ixazomib)是由日本武田制药研制的新一代蛋白酶体抑制剂,2015年11月美国FDA批准其联合来那度胺以及地塞米松,用于既往已接受过至少一种治疗方案的多发性骨髓瘤(MM)的治疗。作为首个口服蛋白酶体抑制剂,依沙佐米为业界普遍看好,其突破了现有蛋白酶抑制剂无法口服的局限性,对改善患者的生活质量具有重要现实意义。笔者就依沙佐米的基本信息、作用机理、药动学、药效学、临床试验及应用等研发动态作一概述,以期为医院临床用药提供一定的指导。     

多发性骨髓瘤治疗药Carfilzomib

蛋白酶体抑制剂carfilzomib（商品名：Kyprolis）于2012年7月获美国FDA批准,用于治疗已使用过包括硼替佐米和免疫调节药物在内的2种以上治疗方案,但在60d内疾病仍有进展的多发性骨髓瘤患者。药理研究表明：该药可与20S蛋白酶体的含苏氨酸N-末端活性位点可逆性结合。     

蛋白酶体抑制剂硼替佐米治疗自身免疫病的研究进展

泛素-蛋白酶体系统是细胞内蛋白降解的主要途径,目前认为这一系统参与多种炎症和自身免疫病的发生,因此,通过阻断泛素调节蛋白降解成为治疗自身免疫病的新方法。此文就蛋白酶体抑制剂硼替佐米治疗自身免疫病的研究进展做一综述。     

硼替佐米致可逆性后部脑病综合征一例并文献复习

硼替佐米是治疗多发性骨髓瘤的蛋白酶体抑制剂类药物,临床治疗中硼替佐米可导致周围神经病变。然而,硼替佐米引起的中枢神经病变却鲜有报道,本文将1例应用硼替佐米后出现意识改变、周身强直性阵挛,最终诊断为可逆性后部脑病综合征的病例进行报道,并对相关文献进行复习,以期提高临床医生对此种不良反应的认识。     

抗肿瘤新靶点USP7及其抑制剂的研究进展

泛素-蛋白酶体系统（UPS）的失控与肿瘤、神经退行性疾病、病毒感染等疾病密切相关,以该系统为导向的药物研发已逐渐引发关注,其中蛋白酶体抑制剂硼替佐米（万珂）作为抗肿瘤药物已成功上市。泛素特异性蛋白酶7（USP7）是UPS中的一种关键性酶,作为去泛素化酶参与细胞内肿瘤抑制、DNA修复及免疫应答等过程中诸多重要蛋白的活性调控。本文介绍泛素特异性蛋白酶7及其抑制剂,强调泛素特异性蛋白酶7抑制剂在抗肿瘤治疗中的潜在应用价值。     

硼替佐米致周围神经病变和急性心衰1例并文献复习

<正>硼替佐米(bortezomib)是一种可逆性的蛋白酶抑制剂[1,2],可选择性地与蛋白酶体活性位点的苏氨酸结合,通过干扰蛋白酶体20S亚单位的糜蛋白酶/胰蛋白酶活性从而影响蛋白质降解。2003年美国食品和药物管理局批准该药用于复发难治性多发性骨髓瘤(multiple myeloma,MM)患者的治疗。目前,以硼替佐米为基础的联合化疗方案,被广泛用于MM患者的一线治疗[3]。但随着临床的     

Antioxidants block proteasome inhibitor function in endometrial carcinoma cells

We have recently demonstrated that proteasome inhibitors can be effective in inducing apoptotic cell death in endometrial carcinoma cell lines and primary culture explants. Increasing evidence suggests that reactive oxygen species are responsible for proteasome inhibitor-induced cell killing. Antioxidants can thus block apoptosis (cell death) triggered by proteasome inhibition. Here, we have evaluated the effects of different antioxidants (edaravone and tiron) on endometrial carcinoma cells treated with aldehyde proteasome inhibitors (MG-132 or ALLN), the boronic acid-based proteasome inhibitor (bortezomib) and the epoxyketone, epoxomicin. We show that tiron specifically inhibited the cytotoxic effects of bortezomib, whereas edaravone inhibited cell death caused by aldehyde-based proteasome inhibitors. We have, however, found that edaravone completely inhibited accumulation of ubiquitin and proteasome activity decrease caused by MG-132 or ALLN, but not by bortezomib. Conversely, tiron inhibited the ubiquitin accumulation and proteasome activity decrease caused by bortezomib. These results suggest that edaravone and tiron rescue cells of proteasome inhibitors from cell death, by inhibiting blockade of proteasome caused by MG-132 and ALLN or bortezomib, respectively. We also tested other antioxidants, and we found that vitamin C inhibited bortezomib-induced cell death. Similar to tiron, vitamin C inhibited cell death by blocking the ability of bortezomib to inhibit the proteasome. Until now, all the antioxidants that blocked proteasome inhibitor-induced cell death also blocked the proteasome inhibitor mechanism of action.     

Design,Synthesis and Biological Evaluation of Peptidyl Epoxyketone Proteasome Inhibitors Composed of β‐amino Acids

A series of novel di‐ and tripeptidyl epoxyketone derivatives composed of β‐amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti‐proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI‐H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC₅₀ values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm . In addition, all the four compounds showed anti‐proliferation activities with IC₅₀ values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e . All the experimental results validated that the β‐amino acid building block has the potential for the development of proteasome inhibitors.     

Ungewöhnliche Baeyer-Villiger-Oxidation mit alkalischer Wasserstoffperoxidlösung

Unusual Baeyer-Villiger Oxidation with Alkaline Hydrogen Peroxide Solution The reaction of nardofuran (1) with alkaline hydrogen peroxide did not provide the expected epoxyketone 2 , but the epoxylactone 3 . Under the conditions applied this is a rare Baeyer-Villiger oxidation product. By lowering the temperature from +15°C to ?15°C and by altering the molar ratio of the reactants, epoxynardofuran 2 was obtained, which is an intermediate in teh formation of 3 .     

Targeting the proteasome pathway

Background: The ubiquitin–proteasome pathway functions as a main pathway in intracellular protein degradation and plays a vital role in almost all cellular events. Various inhibitors of this pathway have been developed for research purposes. The recent approval of bortezomib (PS-341, Velcade^®), a proteasome inhibitor, for the treatment of multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and other components of the ubiquitin–proteasome pathway. Objectives: We review the current understanding of the ubiquitin–proteasome pathway and inhibitors targeting this pathway, including proteasome inhibitors, as candidate drugs for chemical therapy. Methods: Preclinical and clinical data for inhibitors of the proteasome and the ubiquitin–proteasome pathway are discussed. Conclusions: The proteasome and other members in the ubiquitin–proteasome pathway have emerged as novel therapeutic targets.     

Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib

The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib.     

Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism

The role of the proteasome in neurodegenerative diseases is controversial. On the one hand, there is evidence that a dysfunction of proteasome activity can lead to neurodegeneration but there is also data showing that proteasome inhibition can protect nerve cells from a variety of insults. In an attempt to clarify this issue, we studied the effects of four different proteasome inhibitors in a well characterized model of oxidative stress-induced nerve cell death. Consistent with the hypothesis that proteasome inhibition can be neuroprotective, we found that low concentrations of proteasome inhibitors were able to protect nerve cells from oxidative stress-induced death. Surprisingly, the neuroprotective effects of the proteasome inhibitors appeared to be at least partially mediated by the induction of NF-kappaB since protection was significantly reduced in cells expressing a specific NF-kappaB repressor. The activation of NF-kB by proteasome inhibitors was mediated by IkappaB alpha and IKK and was blocked by antioxidants and inhibitors of mitochondrial reactive oxygen species production. These data suggest that low concentrations of proteasome inhibitors induce a moderate level of mitochondrial oxidative stress which results in the activation of neuroprotective pathways.     

Pharmacological proteasome inhibitors and their therapeutic potential

Implication of the proteasome in human cancer, inflammation, autoimmune and other diseases has prompted design, synthesis and evaluation of various pharmacological proteasome inhibitors. In this review, we will summarise the literature related to human cancer cell death induction by proteasome inhibitors, examine the proteasome inhibitor patents published over the past five years and evaluate the potential clinical applications in the use of proteasome inhibitors for treating cancer and other human diseases.     

Development of proteasome inhibitors in oncology and autoimmune diseases

The proteasome is a multicatalytic protease complex that mediates the controlled degradation of intracellular proteins, including key components of pathways that contribute to cancer cell growth and immune cell signaling. Validation for the proteasome as a therapeutic target in oncology was provided by bortezomib, a proteasome inhibitor that was approved for the treatment of multiple myeloma in 2003. Since that time, a number of structurally and mechanistically distinct proteasome inhibitors have entered clinical development in oncology. In this review, the chemical properties, preclinical antitumor activities and early clinical trials of these next-generation proteasome inhibitors are described and the potential for future proteasome inhibitor development in autoimmune indications is discussed.     

新型非共价结合拟肽类蛋白酶体抑制剂的合成及活性评价

目的 设计、合成系列非共价结合拟肽类蛋白酶体抑制剂,并对其进行活性评价。方法 根据非共价结合蛋白酶体抑制剂与蛋白酶体的结合特点,采用氨基酸替换、生物电子等排等经典的药物设计方法,选取邻氯苄胺作为化合物的羧基末端基团,同时在肽骨架结构中引入六元环以增强肽类化合物的稳定性,设计并合成了一系列短肽非共价结合类蛋白酶体抑制剂,并通过体外蛋白酶体活性抑制实验评价该类化合物的活性。结果 共合成了8个具有全新结构的二肽和三肽化合物,其结构经¹H-NMR、ESI-MS确证,该类化合物对蛋白酶体具有中等的抑制活性。结论 肽链的长短及氨基末端不同的取代基对化合物的蛋白酶体抑制活性都有影响,8个化合物在体外对蛋白酶体都具有不同程度的抑制活性。本研究丰富了蛋白酶体抑制剂的结构类型,为该类化合物的深入研究奠定了基础。     

Macrocyclic proteasome inhibitors

Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.