吡唑类细胞周期蛋白依赖性激酶抑制剂的研究进展

细胞周期蛋白依赖性激酶(cyclin-dependent kinases,CDKs)是一类重要的抗肿瘤药物研究靶标。吡唑环作为杂环化合物中的一个重要分支,因其广泛的抗肿瘤活性备受药物化学家关注。近年来大量具有抗肿瘤活性的吡唑类CDKs抑制剂被报道,其中一些化合物已进入临床试验阶段。本文从抑制剂的结构类型出发,对吡唑类CDKs抑制剂的研究进展进行综述。     

细胞周期蛋白依赖性激酶抑制剂（CDKs）中间体的设计与合成

简述了细胞周期蛋白依赖性激酶CDK4抑制剂及其抑制剂的相关概念,详细介绍了细胞周期蛋白激酶的研究进展,重点研究了中间体2一溴-1-（4-吗啉苯基）乙酮的路线选择与合成。4-氟苯乙酮为起始原料,经过溴代反应合成2-溴-1-（4-吗啉苯基）乙酮。依据文献报道,比较不同的合成路线,最终选择先溴代再脱溴的方法合成目标化合物。     

细胞周期素依赖性激酶活性中心残基与其抑制剂相互作用机制研究

以16个2-氨基噻唑衍生物抑制剂为研究对象,利用AutoDock4.2软件进行了分子对接,分析抑制剂分子和细胞周期素依赖性激酶(CDK2)的结合情况。研究结果显示,活性中心残基Leu83主干上的羰基和氨基分别与抑制剂分子C9原子上的氨基和噻唑环上的N原子形成氢键,Glu81主干上的羰基和抑制剂分子C8上的氨基形成氢键,Phe80侧链上苯基和抑制剂母体分子上的苯基形成了π-π堆积作用,CDK2通过与抑制剂分子之间形成的氢键网络和π-π堆积作用将小分子固定在CDK2的活性中心。     

细胞周期蛋白依赖性激酶4重组蛋白兔血清抗体的制备及鉴定

目的 制备细胞周期蛋白依赖性激酶4(cyclin-dependent kinase 4,CDK4)重组蛋白兔血清抗体并鉴定其特性.方法 将设计合成的CDK4基因克隆至载体pET21a(+)中,构建重组质粒pET21a(+)/CDK4,转化至大肠埃希菌BL21(DE3)中,IPTG诱导表达,表达产物经镍螯合亲和层析纯化,...     

多烯紫杉醇诱导细胞周期阻断与凋亡过程的模型

以多烯紫杉醇诱导白血病细胞株K562为对象,建立了描述肿瘤细胞生长及其与药物作用关系的细胞周期数学模型,研究了多烯紫杉醇诱导K562细胞周期变化与凋亡现象及量效关系.结果表明,多烯紫杉醇引起K562细胞M期阻断和诱导细胞凋亡的饱和浓度分别为17.96、7.82 nmol·L-1,有效浓度分别为2.63、1.69 nmol·L^-1;低浓度（1.69～2.63 nmol·L^-1）的多烯紫杉醇直接诱导细胞凋亡而不引起明显的M期阻断;高浓度（>7.82 nmol·L^-1）的多烯紫杉醇主要效应是促进细胞M期阻断.本模型揭示出M期阻断与凋亡无显著的相关性,为多烯紫杉醇的作用机制提供了一个新的解释.     

光谱法在癌症诊断中的应用

癌症是导致人类死亡的重大疾病之一,严重的危害人类的生命健康。实验研究表明,现今有效治愈癌症的能力直接取决于癌症早期检出的能力。光谱技术（诸如：质谱法、红外光谱法、拉曼光谱、荧光光谱法等等）作为一种检测方法,广泛应用于癌症的早期诊断方面的研究,为癌症的医学诊断提供了理论依据,本文对光谱法在癌症早期诊断中的应用作一简单介绍。     

透明质酸对人骨性关节炎软骨细胞凋亡及细胞周期的影响

目的观察透明质酸(Hyaluronic acid,HA)对人骨性关节炎(Osteoarthritis,OA)软骨细胞凋亡及细胞周期的影响,以探讨HA保护软骨细胞的作用机制。方法分离人正常软骨细胞和OA软骨细胞,传至第2代后,分别经HA处理24 h,采用MTT法检测细胞的增殖活力,流式细胞术检测细胞凋亡率和细胞周期。结果 HA能明显降低人OA软骨细胞的凋亡率(P<0.05),提高细胞的增殖活力、S期比例和增殖指数(P<0.05),且对正常人软骨细胞的增殖活力和凋亡无明显影响。结论 HA可促进OA软骨细胞的分裂与增殖,降低细胞凋亡率,从而对软骨细胞发挥保护作用。     

Aurora-A激酶抑制剂VX-680对食管癌细胞凋亡的影响

目的探讨Aurora-A激酶抑制剂VX-680对食管鳞癌EC9706细胞凋亡的影响。方法用不同浓度的VX-680(10、30、50、100 nmol/L)处理EC9706细胞48 h,并设DMSO对照组和空白对照组,倒置显微镜下观察细胞形态的变化,CCK-8法检测细胞的存活率,流式细胞术检测细胞的凋亡率。结果随着VX-680浓度的增加,贴壁细胞逐渐出现皱缩、变圆、脱落等现象;细胞存活率呈逐渐下降趋势(P0.01);细胞凋亡率均高于DMSO对照组,且50和100 nmol/L VX-680组细胞凋亡率与DMSO对照组比较,差异有统计学意义(P0.01)。结论 VX-680能促进EC9706细胞凋亡,在食管癌临床治疗方面具有良好的应用前景。     

紫草素衍生物诱导肺癌细胞A549细胞周期阻滞及细胞凋亡

以1,4-二甲氧基苯和马来酸酐为原料,合成5,8-二甲氧基萘-1,4-二酮,通过加成反应分别制备亚砜和氨基的2-取代萘醌类衍生物a和b,采用MTT实验检测两种化合物诱导肺癌细胞A549细胞周期阻滞及细胞活性,探讨二者的结构与活性关系,并阐述其导致细胞周期阻滞及细胞凋亡的具体作用机制。结果证明,化合物a通过激活抑癌基因P53及丝裂原活化蛋白激酶信号通路对A549细胞增殖有显著抑制作用,同时可以显著促进细胞凋亡;而化合物b并无显著作用。     

Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib,Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment

The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.     

Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.     

Cyclin-Dependent Kinase Synthetic Lethality Partners in DNA Damage Response

Cyclin-dependent kinases (CDKs) are pivotal mediators and effectors of the DNA damage response (DDR) that regulate both the pathway components and proteins involved in repair processes. Synthetic lethality (SL) describes a situation in which two genes are linked in such a way that the lack of functioning of just one maintains cell viability, while depletion of both triggers cell death. Synthetic lethal interactions involving CDKs are now emerging, and this can be used to selectively target tumor cells with DNA repair defects. In this review, SL interactions of CDKs with protooncogene products MYC, poly (ADP-ribose) polymerase (PARP-1), and cellular tumor antigen p53 (TP53) are discussed. The individual roles of each of the SL partners in DDR are described.     

A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening,Molecular Docking,and Molecular Dynamic Simulations

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.     

Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.     

Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.     

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

Drug resistance continues to be a major problem associated with cancer treatment. One of the primary causes of anticancer drug resistance is the frequently mutated RAS gene. In particular, considerable efforts have been made to treat KRAS-induced cancers by directly and indirectly controlling the activity of KRAS. However, the RAS protein is still one of the most prominent targets for drugs in cancer treatment. Recently, novel targeted protein degradation (TPD) strategies, such as proteolysis-targeting chimeras, have been developed to render “undruggable” targets druggable and overcome drug resistance and mutation problems. In this study, we discuss small-molecule inhibitors, TPD-based small-molecule chemicals for targeting RAS pathway proteins, and their potential applications for treating KRAS-mutant cancers. Novel TPD strategies are expected to serve as promising therapeutic methods for treating tumor patients with KRAS mutations.     

BCR-ABL络氨酸激酶抑制剂类药物的研究进展

BCR-ABL络氨酸激酶与慢性粒细胞白血病(CML)的发生密切相关,以其为靶点的激酶抑制剂成为近年来抗CML药物的研发热点。与传统药物相比,此类药物具有选择性高、副作用少的特点,部分已经成为治疗慢性粒细胞白血病的一线用药。文章从作用机制、临床适用范围和国内外上市开发状况等方面,对BCR-ABL络氨酸激酶抑制剂类药物的研究进展进行了综述。     

The Complexities of Epidemiology and Prevention of Gastrointestinal Cancers

Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate of cancer significantly; this is why it is important to delineate the underlying causes. It has been well recognized that genetic mutations, sporadic or hereditary, may lead to increased chance of tumorigenesis. Detecting genetic mutations can lead to the identification of high-risk individuals with hereditary cancer syndromes, which may assist in devising prevention strategies. Further, environmental factors are known to play important roles in epidemiology and suggest prevention tools that could be implemented to reduce cancer incidence and subsequent cancer-associated morbidity and mortality. Chemoprevention has been tried in colon cancer and is finding new advancements in other carcinomas as well. Out of many environmental cancer preventive agents, the most notable developments are the identification of the role of vitamins E, vitamin D and folic acid. Increased consumption of these vitamins has shown to be inversely correlated with cancer risk. This review will highlight important aspects of cancer epidemiology in the most aggressive carcinomas of the gastrointestinal system focusing on colorectal adenocarcinoma and pancreatic adenocarcinoma. Additionally, some of the well-known and evolving aspects of epidemiology of colorectal and pancreatic cancer along with current and new prevention strategies will also be reviewed.