Expression of cyclin-dependent kinase inhibitor 2A 16,tumour protein 53 and epidermal growth factor receptor in salivary gland carcinomas is not associated with oncogenic virus infection

It is known that human papillomavirus （HPV） infection can cause squamous cell neoplasms at several sites, such as cervix uteri carcinoma and oral squamous carcinoma. There is little information on the expression of HPV and its predictive markers in tumours of the major and minor salivary glands of the head and neck. We therefore assessed oral salivary gland neoplasms to identify associations between HPV and infection-related epidermal growth factor receptor （EGFR）, cyclin-dependent kinase inhibitor 2A （CDKN2A/p16） and tumour protein p53 （TP53）. Formalin-fixed, paraffin-embedded tissue samples from oral salivary gland carcinomas （n=51） and benign tumours （n=26） were analysed by polymerase chain reaction （PCR） analysis for several HPV species, including high-risk types 16 and 18. Evaluation of EGFR, CDKN2A, TP53 and cytomegalovirus （CMV） was performed by immunohistochemistry. Epstein-Barr virus （EBV） was evaluated by EBV-encoded RNA in situ hybridisation. We demonstrated that salivary gland tumours are not associated with HPV infection. The expression of EGFR, CDKN2A and TP53 may be associated with tumour pathology but is not induced by HPV. CMV and EBV were not detectable. In contrast to oral squamous cell carcinomas, HPV, CMV and EBV infections are not associated with malignant or benign neoplastic lesions of the salivary glands.

Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response(pCR) is rare in hormone receptor-positive(HR+)HER2-negative breast cancer(BC) treated with either endocrine therapy(ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures.The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced p CR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a p CR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified asendocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.

High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.

Tolerance of neurite outgrowth to Rho kinase inhibitors decreased by cyclooxygenase-2 inhibitor

In this study, PC12 Adh cells and Neuro-2a cells were treated with Rho-associated kinase inhibitors （Y27632 and Fasudil）, a cyclooxygenase-1 selective inhibitor （SC560）, and a cyclooxygenase-2 inhibitor （NS398）. We found that these cells became tolerant to Rho-associated kinase inhibitors, as neurite outgrowth induced by these inhibitors diminished following more than 3 days of exposure in either cell line. The proteins cyclooxygenase-2 and cytosolic prostaglandin E synthetase were upregulated at day 3. NS398 decreased the tolerance to neurite outgrowth induction in both cell lines, whereas SC560 had almost no effect. These findings indicate that cells become tolerant to neurite outgrowth induced by Rho-associated kinase inhibitors, this is at least partly associated with upregulation of proteins involved in the cyclooxygenase-2 pathway, and cyclooxygenases-2 inhibition prevents this tolerance.

Synthesis of 5-substituted benzyl-2,4-diamino pyrimidine derivatives as c-Fms kinase inhibitors

A serials of novel 5-substituted benzyl-2,4-diamino pyrimidine derivatives have been synthesized and evaluated as inhibitors of c-Fms kinase by the standard MTT method.The results showed that compound 15,5-[3-methoxy-4-（pyridine-3-yl）benzyl]-2,4-diamino pyrimidine,had an IC50 of 1.45μmol/L in inhibiting the proliferation of M-CSF-dependent myeloid leukemia cells in mice （NFS-60）,which was similar with GW2580,a selective inhibitor of c-Fms kinase.

TYK2抑制剂的研究进展

TYK2(酪氨酸激酶2)作为Janus激酶家族的一员,在IL-12、IL-23和I型IFN等细胞因子的调控中扮演着重要的角色。鉴于JAK抑制剂选择性不高而产生不良反应等问题,靶向TYK2蛋白抑制剂的研发正逐步受到科研工作者的重视。本文从TYK2蛋白的结构特征出发,先后介绍了靶向TYK2激酶结构域(JH1)的底物竞争性抑制剂和靶向假激酶结构域(JH2)的变构抑制剂以及TYK2降解剂,为以后TYK2抑制剂的研究提供新的参考。

Transcriptional regulation of human polo-like kinases and early mitotic inhibitors

Human polo-like kinases （PLK1-PLK4） have been implicated in mitotic regulation and carcinogenesis. PLK1 phosphorylates early mitotic inhibitor 1 （Emil） to ensure mitosis entry, whereas Emi2 plays a key role during the meiotic cell cycle. Transcription factor E2F is primarily considered to regulate the G1/S transition of the cell cycle but its involvement in the regulation of mitosis has also been recently suggested. A gap still exists between the molecular basis of E2F and mitotic regulation. The present study was designed to characterize the transcriptional regulation of human PLK and Emi genes. Adenoviral overexpression of E2F1 increased PLK1 and PLK3 mRNA levels in A549 cells. A reporter gene assay revealed that the putative promoter regions of PLK1, PLK3, and PLK4 genes were responsive to activators E2F, E2F1-E2F3. We further characterized the putative promoter regions of Emil and Emi2 genes, and these could be regulated by activators E2F and E2F1-E2F4, respectively. Finally, PLK1-PLK4, Emil, and Emi2 mRNA expression levels in human adult, fetal tissues, and several cell lines indicated that each gene has a unique expression pattern but is uniquely expressed in common tissues and cells such as the testes and thymus. Collectively, these results indicate that E2F can integrate G1/S and G2/M to oscillate the cell cycle by regulating mitotic genes PLK and Emi, leading to determination of the cell fate.

Down-regulation of transforming growth factor β1/activin receptor-like kinase 1 pathway gene expression by herbal compound 861 is related to deactivation of LX-2 cells

AIM: To investigate the effect of herbal compound 861 (Cpd861) on the transforming growth factor-β1 (TGFβ1)/ activin receptor-like kinase 1 (ALK1, type Ⅰ receptor) signaling-pathway-related gene expression in the LX-2 cell line, and the inhibitory mechanism of Cpd861 on the activation of LX-2 cells. METHODS: LX-2 cells were treated with TGFβ1 (5 ng/mL) Cpd861 (0.1 mg/mL), TGFβ1 (5 ng/mL) plus Cpd861 (5 ng/mL) for 24 h to investigate the effect of Cpd861 on the TGFβ1/ALK1 pathway. Real-time PCR was performed to examine the expression of α-SMA (α-smooth muscle actin), ALK1, Id1 (inhibitor of differentiation 1). Western blotting was carried out to measure the levels of α-SMA and phosphorylated Smad1, and immunocytochemical analysis for the expression of α-SMA. RESULTS: In LX-2 cells, TGFβ1/ALK1-pathway-related gene expression could be stimulated by TGFβ1, which led to excessive activation of the cells. Cpd861 decreased the activation of LX-2 cells by reducing the expression of α-SMA mRNA and protein expression. This effect was related to inhibition of the above TGFβ1/ALK1-pathway- related expression of genes such as Id1 and ALK1, and phosphorylation of Smad1 in LX-2 cells, even with TGFβ1 co-treatment for 24 h. CONCLUSION: Cpd861 can restrain the activation of LX-2 cells by inhibiting the TGFβ1/ALK1/Smad1 pathway.

JAK1/2抑制剂治疗成人皮肌炎的疗效和安全性评价

目的:评价JAK抑制剂治疗成人皮肌炎(DM)患者的疗效和安全性。方法:收集2020年5月至2022年12月,在南方医科大学皮肤病医院皮肤科门诊就诊的DM患者。开始治疗前由皮肤科医生完成DM皮损范围和严重程度指数(CDASI)评分,同时留取患者皮疹照片并行血常规、生化指标、抗核抗体、抗核抗体谱、肌炎特异性抗体检查,除外禁忌后予口服JAK1/2抑制剂2 mg/d治疗12周。治疗开始后于第4、8、12周随访,评估CDASI评分,复查相关指标,并记录出现的不良反应事件。结果:纳入7例DM患者,6例患者完成12周的药物治疗和随访观察。CDASI评分开始治疗后均呈持续下降趋势,持续改善可维持至第12周。治疗12周后,部分有肌痛和/或肌无力的患者症状得到改善。部分患者肌酶指标下降,但无统计学意义。随访期间患者无严重不良反应。结论:JAK1/2抑制剂有望成为激素控制不佳、需使用激素或其他系统药物的成人DM患者治疗的新选择。

针灸预处理对胃溃疡大鼠胃黏膜状态及Gli 1/Gli 2/Sufu信号通路的影响研究

目的:研究针灸预处理对胃溃疡大鼠胃黏膜状态及胶质瘤相关癌基因同源物1(Glioma-associated oncogene homolog 1,Gli1)/胶质瘤相关癌基因同源物2(Glioma-associated oncogene homolog 2,Gli2)/丝氨酸/苏氨酸激酶Fused抑制物(Sufu)信号通路的影响,探究针灸预防胃黏膜损伤的作用机制,为针灸在临床治疗胃溃疡疾病提供实验依据和理论支撑。方法:52只大鼠随机分为正常组、模型组、灸预处理组、针刺预处理组,每组13只。正常组、模型组只做固定;对灸预处理组和针刺预处理组艾灸中脘、足三里穴,每穴20min,1次/d,连续灸8d。之后对灸预处理组和针刺预处理组大鼠进行无水乙醇+阿司匹林混悬液灌胃造模。观察大鼠一般情况及胃黏膜组织病理学变化;酶联免疫吸附实验(ELISA)法检测大鼠血清中超氧化物歧化酶(SOD)、丙二醛(Malondialdehyde,MDA)、谷胱甘肽过氧化物酶(GPX)浓度,蛋白质印迹法(Western blot)分析大鼠胃黏膜组织Gli 1、Gli 2、Sufu蛋白表达。结果:模型组可见上皮细胞结构破坏不完整,胃黏膜组织损伤明显,UI指数评分显著高于正常组(P<0.05)。与正常组比较,模型组大鼠血清MDA、GPX浓度升高(P<0.05),SOD浓度降低(P<0.05);与模型组相比,针灸预处理组MDA、GPX浓度降低(P<0.05),SOD浓度增加(P<0.05);与正常组比较,模型组大鼠Gli1、Gli2、Sufu蛋白表达明显升高(P<0.05);与模型组比较,针灸预处理组大鼠Gli1、Gli2、Sufu蛋白表达明显降低(P<0.05)。结论:针灸预处理能改变胃溃疡大鼠胃黏膜状态,其机制可能与Gli 1/Gli 2/Sufu信号通路活化有关。

IKBKE、YAP1和TEAD2在结直肠癌中的表达及临床意义

目的探讨核因子κb激酶亚基ε的抑制剂(IKBKE)、Yes相关蛋白1(YAP1)和转录增强结构域转录因子2(TEAD2)在结直肠癌(CRC)组织中的表达及其临床意义。方法收集2016年1月至2017年12月在蚌埠医科大学第一附属医院手术切除的142例CRC组织及对应癌旁组织,采用免疫组化法检测标本中IKBKE、YAP1和TEAD2的表达情况。分析3种蛋白在CRC组织中表达的相关性,分析蛋白阳性率与患者临床病理参数及预后的关系;绘制Kaplan-Meier生存曲线,比较这些蛋白不同表达情况患者的生存差异。采用Cox回归分析影响患者预后的危险因素。结果CRC组织中IKBKE、YAP1和TEAD2的阳性率均显著高于癌旁组织(65.5%比9.9%,73.9%比14.1%,66.9%比8.5%,均P<0.05)。IKBKE的表达与肿瘤的分化程度、浸润深度、淋巴结转移、肿瘤-淋巴结-远处转移(TNM)分期有关,YAP1和TEAD2的表达均与肿瘤的分化程度、浸润深度、淋巴结转移、远处转移及TNM分期有关。Spearman秩相关分析显示CRC组织中IKBKE与YAP1、TEAD2表达均呈正相关(均P<0.01)。Kaplan-Meier生存分析显示IKBKE、YAP1和TEAD2阳性表达组的总生存率降低。Cox回归分析显示IKBKE、YAP1和TEAD2阳性、肿瘤分化程度高、TNM分期高是CRC患者预后的独立危险因素。结论CRC中IKBKE、YAP1和TEAD2阳性表达与肿瘤的分化程度、TNM分期、转移等因素有关,可能成为CRC治疗的潜在靶点;检测这3个蛋白的表达有助于评估预后。

小分子酪氨酸激酶抑制剂A2B通过调控PI3K/Akt通路诱导胃癌细胞凋亡

目的:探讨小分子酪氨酸激酶抑制剂A2B诱导人胃癌SGC-7901细胞凋亡的分子机制。方法:体外培养人胃癌SGC-7901细胞并加入2.5~160μmol/L梯度浓度的A2B分别干预24、48和72 h,利用CCK-8法检测细胞活力的半数抑制浓度(IC50),筛选出药物最适浓度。后续实验将SGC-7901细胞随机分为对照组(正常培养组)、溶剂组(含0.08%DMSO培养液处理)、A2B 10μmol/L实验组和A2B 20μmol/L实验组,每组每项实验均重复3次。利用EdU细胞染色实验和平板集落形成实验检测各组细胞增殖能力;Annexin V-FITC/PI双染法检测各组细胞凋亡率;线粒体膜电位检测试剂盒(JC-1染色法)检测各组细胞线粒体膜电位变化;Western blot检测各组细胞中表皮生长因子受体(EGFR)、人表皮生长因子受体2(HER2)、细胞间充质-表皮转化因子(c-Met)、B细胞淋巴瘤2(Bcl-2)、Bcl-2相关X蛋白(Bax)、caspase-3、cleaved caspase-3、蛋白激酶B(PKB/Akt)和磷酸化Akt(p-Akt)蛋白的表达情况。结果:(1)A2B作用于人胃癌SGC-7901细胞24、48和72 h的IC50值分别为26.85、19.58和12.24μmol/L;(2)20μmol/L A2B能够同时下调EGFR、HER2和c-Met蛋白水平(P<0.01);(3)10和20μmol/L A2B作用于SGC-7901细胞后,EdU+细胞数和集落数均显著减少(P<0.01);(4)经A2B处理后SGC-7901细胞凋亡率增加(P<0.05),JC-1绿色荧光比例增加(P<0.01),同时Bax/Bcl-2比值和cleaved caspase-3蛋白表达水平上调(P<0.05),caspase-3蛋白表达水平下调(P<0.05);(5)A2B还下调了SGC-7901细胞中p-Akt/Akt比值(P<0.05)。结论:A2B能够靶向作用于EGFR、HER2和c-Met,并通过抑制PI3K/Akt信号通路激活,诱导人胃癌SGC-7901细胞发生凋亡。

Discovery of 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine as Novel Cyclin-dependent Kinases 4 and 6 Dual Inhibitors via 3D-QSAR and Molecular Simulation

Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs.In this article,3D-QSAR modeling including comparative molecular field analy-sis(CoMFA)and comparative molecular similarity indices analysis fields(CoMSIA)was implemented on 52 dual CDK4/6 inhibitors.As a result,we obtained a pretty good 3D-QSAR model,which is CoMFACDK4 with q2 to be 0.543 and r^(2) to be 0.967;CoMSIACDK4 with q2 being 0.518 and r^(2) being 0.937;CoMFACDK6 with q2 to be 0.624 and r^(2) to be 0.984;CoMSIACDK6 with q2 being 0.584 and r^(2) being 0.975.Molecular docking confirmed the important residues for interactions.Molecular dynamics simulation further confirmed binding affinity with key residues of protein,such as Lys22,Lys35,Val96 for CDK4 and Lys43,His100,Val101 for CDK6 at the active sites.Then these results offered new directions to explore new inhibitors of CDK4/6.Finally,we designed 10 novel compounds with promising expected activity and ADME/T properties,and provided referable synthetic routes.

酪氨酸激酶抑制剂在HER2阳性乳腺癌中应用的可视化分析

目的分析酪氨酸激酶抑制剂(TKIs)治疗人表皮生长因子受体2(HER2)阳性乳腺癌的研究现状、热点和发展趋势。方法在Web of Science核心合集数据库中检索TKIs治疗HER2阳性乳腺癌的相关文献,使用CiteSpace 6.1.R3软件对发文作者、国家/地区、机构、学科领域、期刊、关键词进行可视化分析。结果共纳入732篇文献,发文量呈逐年上升趋势,以美国发文最多(中心度0.10),我国发文量排第2位(中心度0.05)。发文量和被引频次最多的作者分别是澳大利亚圣文森特大学医院的Crown和美国加州大学洛杉矶分校的Slamon;发文量最多的机构是美国得克萨斯大学安德森癌症中心,最多的期刊是美国Journal of Clinical Oncology;研究热点主要集中在HER2阳性乳腺癌治疗药物、TKIs作用受体、TKIs作用机制、HER2阳性乳腺癌脑转移、TKIs临床研究5个方面;前沿领域和发展趋势主要为TKIs与其他药物或治疗手段联用以增强靶向性并降低毒副作用。结论TKIs治疗HER2阳性乳腺癌的研究受到国内外学者的重视。我国学者和研究团队未来需要加强合作交流,可从TKIs单用及联合用药治疗HER2阳性乳腺癌的疗效及安全性方面加强与其他国家的合作。

果蝇zeste基因增强子的人类同源物2促进小细胞肺癌化疗耐药的作用及其分子机制

目的:观察果蝇zeste基因增强子的人类同源物2(Enhancer of zeste homologue 2,EZH2)对小细胞肺癌(Small cell lung cancer,SCLC)化疗耐药的影响并研究其潜在分子机制。方法:首先使用RT-PCR和蛋白印迹方法检测SCLC初治和耐药患者组织标本、敏感细胞株(H446)和耐药细胞株(H446DDP)的EZH2表达差异;再通过CCK8方法检测敲低EZH2后的耐药SCLC细胞株对化疗药物半抑制浓度(Half maximal inhibitory concentration,IC50)值变化;最后通过RNA测序和验证方法筛查EZH2的下游靶基因以及CHIP-qPCR方法检测EZH2敲低后其靶基因启动子区的EZH2表达变化。结果:SCLC化疗耐药患者EZH2阳性表达水平(80%)高于化疗敏感患者,耐药细胞株(H446DDP)的EZH2 mRNA和蛋白表达水平均高于敏感细胞株(H446)(P<0.01,P<0.001);敲低EZH2表达后,耐药SCLC细胞株对化疗药物IC50值降低;细胞周期蛋白依赖性激酶抑制剂-1A(Cyclin-Dependent Kinase Inhibitor 1A,CDKN1A)表达增加,且CDKN1A基因启动子EZH2蛋白沉积显著减少。结论:EZH2促进SCLC化疗耐药,其分子机制与EZH2靶向调控CDKN1A基因表达相关。

Discovery of a novel eEF2K inhibitor （BL-EKI03） that induces ER stress, autophagy and apoptosis in breast cancer

Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase （eEF2K） activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. Therefore, eEF2K may contribute to carcinogenesis and represent a promising therapeutic target; however, inhibi- tion of eEF2K for cancer drug discovery still remains in its infancy. This study aimed at developing a series of eEF2K inhibitor as candidate anti-tumor drugs in breast cancer and illustrating the possible mechanisms of its anti- tumor activity in vitro and in vivo. Methods In silico screening, structure modifications, MTT assay and molecular dynamics （MD） simulations were applied for the discovery of the novel eEF2K inhibitor （BL-EKI03）. Observa- tions of cell morphology were executed through several methods including ER-traeker, MDC and Hoeehst 33258 staining and GFP-LC3 transfeetion. Flow eytometrie analyses of MDC and Annexin V/PI were used for quantifica- tion of autophagy and apoptosis ratio. Western blot and ITRAQ analysis were used to explore the detailed mecha- nisms of BL-EKI03-induced ER stress, autophagie death and apoptosis in breast cancer cells. Furthermore, an in vivo xenograft mouse model was established for validating the anti-tumor efficacy of BL-EKI03. Results Firstly, a novel eEF2K inhibitor （BL-EKI03） with a good affinity for eEF2K was eventually discovered after computational screening and synthesis of a series of candidate compounds targeting eEF2K. Subsequently, our results demonstra- ted that BL-EKI03 has remarkable anti-proliferative activities and induces endoplasmie retieulum （ER） stress, au- tophagy and apoptosis in MCF-7 and MDA-MB-436 cells. More importantly, the mechanism for BL-EKI03-indueed autophagie death involves eEF2K-mediated AMPK-mTOR-ULK complex pathways. The proteomies analyses and ex-perimental validation revealed that the BL-EKI03-induced mechanism was also involved BIRC6, BNIP1, SNAP29 and Bif-1, which might be regulated by eEF2K. Moreover, BL-EKI03 exerted its anti-tumor activities without re- markable toxicity, and it also induced autophagy and apoptosis by targeting eEF2K in fifo. Conclusion In this study, a novel eEF2K inhibitor （BL-EKI03） was discovered with remarkable anti-proliferative activities and in- duced endoplasmic reticulum （ER） stress, autophagy and apoptosis of breast cancer in vitro and in fifo. These findings highlight a new small-molecule eEF2K inhibitor （BL-EKI03） that has the potential to impact future breast cancer therapy.

Synthesis and biological evaluation of novel 2,4,5-triaryl-1 H-pyrazol-3(2H)-ones as inhibitors of ALK5

A series of 2,4,5-triaryl substituted 1H-pyrazol-3（2H）-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1μmol/L and displayed no significant cytotoxicities at 30μmol/L.

酪氨酸激酶2抑制剂治疗斑块型银屑病机制与临床研究进展

斑块型银屑病是一种免疫相关的慢性炎症性皮肤病,较为常见,疾病负担重,严重影响患者身心健康。近十余年,生物制剂治疗银屑病取得了突破性进展,但安全高效的靶向口服药物仍有待开发。JAK-STAT信号转导途径通过转导细胞因子信号,在多种免疫相关疾病发生发展中具有重要作用。在JAK家族成员中,酪氨酸激酶2已被证实可以通过转导白介素-12/23、干扰素及其下游信号通路,参与斑块型银屑病的发生发展,是较为理想的药物靶点。高度选择性酪氨酸激酶2抑制剂氘可来昔替尼Ⅲ期临床试验显示出良好的疗效和安全性,已获美国食品药品管理局批准用于口服治疗斑块型银屑病,另有多种酪氨酸激酶2抑制剂目前正在研发中。本文介绍了JAK-STAT通路及酪氨酸激酶2参与斑块型银屑病发病的机制,及酪氨酸激酶2抑制剂在斑块型银屑病治疗领域的临床试验现状。

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.