抗癌药研究ppt课件.ppt

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1、Anti-cancer Drug Discovery and Development,疟铬希缮流窝亥迭怎椎抚熬踩勤章卢嚼皮氮涅椅解浴抡乃姜胖碧鄂涯愧莽抗癌药研究ppt课件抗癌药研究ppt课件,Outline,Anti-cancer drug discovery processThe approach to anti-cancer drug discoveryIdentification and validation of targetComputer aided drug design Small Moleculars screening through HTSMetabolic and Ph

2、ysicochemical Profiling of drugCancer resistance,罗拂茅秧骏惧涂昆证次懊畦吉臃涵酿赘垢延城纫滔附惋秒琅寓博橙让纲坪抗癌药研究ppt课件抗癌药研究ppt课件,Anti-cancer drug discovery process,Modern molecular biology and genomics/proteomics to identify and validate new therapeutic targetsCombinatorial chemistry for the efficient generation of structural

3、 diversity and for rapid production of a library of structural analogues based on an identified lead compound and optimization,enhanced structural biology and molecular modeling techniques for rational drug design Robotic high-throughput screening against structurally diverse chemical libraries to d

4、iscover lead drugsHigh-throughput pharmacokinetics assays,the use of surrogate end points to monitor pharmacodynamics throughout thediscovery and development process,particularly involving genomics(e.g.,nucleic acid microassays)and proteomics,乓屯朝干帚椅失掐茎屯汰拯府肚糟发浊诌乒卫讫脸蹲痢亿鞍舀徘情壶组姆抗癌药研究ppt课件抗癌药研究ppt课件,The

5、approach to anti-cancer drug discovery,cell-based screeningTargeting the specific molecular lesions,娘亩呆莲磺枣随雄贪沤蹋鄂诱碴组界鲁司吵欲肤沂讽恬州割捍盼寿秸修赐抗癌药研究ppt课件抗癌药研究ppt课件,Cell-based screening,1.cell-based cytotoxicity assays:random high-throughput screening of synthetic compounds and natural products,based on anti-pr

6、oliferative effects 2.synthetic compounds and natural products belong to DNA-damaging agents with a low therapeutic index,Not target the molecular lesions responsible for malignant transformation NCI:highly chemo-sensitive P388 leukemia cell line,伯合残乓鹤殿跺抬训崖纫煤食赏蚜笛掀浚诺纤翅漆层晋踊藤宴矣漱疡咬索抗癌药研究ppt课件抗癌药研究ppt课件,

7、Target-based screening for anti-cancer drug discovery,Identification and validation of targetEmerging targetsDrug design and HTS,邻辫解袍聊瑚诅符意侵稍耍酿驹岿洽踪禾手炔桐端铭乞向庄卢惑浴剐烬刮抗癌药研究ppt课件抗癌药研究ppt课件,Identification and validation of target,Genomics analytic technology:microarray analysis,high-throught RNAi,Ambion,Inc

8、.Cenix BioScience Proteomics analytic technology:affinity chromatography and mass spectrometry X-omics analytic technology Epigenomics(DNA methylation and histone deacelylation),Cytomics,Metabolomics,Interatomics,Bioinformomics,细粤沛患橙杏糠胖幌脱杖朋侥胚姜诣厌史钡涧氢拨荤绵锣割瑰琶踏鞍粉筑抗癌药研究ppt课件抗癌药研究ppt课件,Emerging targets,On

9、cogenes and apoptosis-inhibiting genes,mainly encoding proteins that are components of signal transduction pathways that regulate proliferation,differentiation,invasion/metastasis,angiogenesis and/or tumor apoptosis or cell death Targets facilitating tumor-microenvironment interactions and metastasi

10、sthe Moffitt Cancer Center Drug Discovery Program at the University of South FloridaUniversity of Illinois:FoxM1 Inhibitors are Anticancer Drugs that Induce Cell Death,痞蒜墙脓夺崭轿亲域愤樱努祷毗赴寅通梅察嘲诞收匣暗氯痪两从抛平斡隐抗癌药研究ppt课件抗癌药研究ppt课件,targeting Wnt signaling miRNAs,Hedgehog signalingthe Notch pathway metabolic pa

11、thwaysthe immune systemspecific inflammatory mediatorsTGF signaling pathwaymacrophage stimulating protein(MSP)and its receptor RonRho GTPase signaling networkthe IGF signaling networkApoptosis and cell cycle:Ras,a GTPase,Raf/Mek,Erk1/2,PI3K/Akt,p53,CDK4,CDK4 activator cyclin D1,CDK4 inhibitor p16,Bc

12、l-2 genes,悬藕卓抹希逆军捡壕抨诱湃蛀涛龟抠贿皖舞公源牌厦墩恒彼专锤联迹嗓选抗癌药研究ppt课件抗癌药研究ppt课件,Structure-Based Drug Design&Virtual Screening,X-ray crystal structures and/or homology modelsVirtual screening(VS)technologies:computationally“dock”small molecules into the active sites of our molecular targets Visualize and probe molecu

13、lar interactions in 3D using advanced computational graphics systems to understand the forces that contribute to enhanced binding,肾裸赶承成余艾韶挟挂旺瘸畔哭麓买疽悟蕴借扔菊甘箍裸赶薪亨缓跺词斌抗癌药研究ppt课件抗癌药研究ppt课件,High-Speed Analoging:parallel synthesis and high-throughput purification techniques coupled with computational chemis

14、try input,enables the rapid generation of intelligently designed iterations of novel compound libraries to expedite our“HTS hit-to-lead”and“lead optimization”drug discovery processesstrong hardware platform,state-of-the-art software suites,帧枷介肆型源铅转害风坐拨憨栖稼杀孟浅靛肘绑丝骏捶互娄菇育辗父甫背抗癌药研究ppt课件抗癌药研究ppt课件,High-th

15、roughput Screening(HTS),Incubating the target protein with mixtures of up to 500 compounds at a time.Size Exclusion chromatography(SEC):seperating hits from unbound compounds mass spectrometry(LC-MS):identifying the binders An industrial-scale robotic cherry-picker retrieves orders of screening“hits

16、”for confirmation testing within 24 hours,焰台码钟承酮绘实拙礁敦詹融乎匿铭严霓舰舷橱足齐顺啤后屉狈杏灭浓泵抗癌药研究ppt课件抗癌药研究ppt课件,Metabolic and Physicochemical Profiling,Solubility and permeability,how well a drug is absorbedMetabolization by subcellular liver microsomes Predict possible drug-drug interactions,testing their inhibitor

17、y effect on cytochrome P450 enzymes Identify those compounds that have the greatest chance of succeeding as drugsMolecular Imaging,luminescence and fluorescence imaging,visualize and quantitate non-invasively specific molecular targets,biochemical pathways and physiological effects of novel drug can

18、didates in vivo,瓣红耿狱硼抖炔身咋夹论攻凉央砒帧于完朋衷醇简身哨脏酝窝云糯军藩鳞抗癌药研究ppt课件抗癌药研究ppt课件,Success molecularly targeted drugs,All-trans-retinoic acid for acute promyelocytic leukemiaimatinib(STI-571)for chronic myelogenous leukemia,盈浸吗互撮堪幻儡啥玉跋耗汤箍凝劲雁资密锭框君存幢箱晋缸扰扎滑塞努抗癌药研究ppt课件抗癌药研究ppt课件,target-based screening for anti-cance

19、r drug discovery,Shortcomings:Can not discover a small molecule that restores protein functionPharmacologic effect of the compound at a cellular or organism level maybe influencedSolution:Again doing Cell-based assays 1.drugs pharmacologic effects at the cellular level 2.discovery new targets Target

20、-based and cell-based screening for new anticancer drugs in the molecular targeting era are complementary methods,颗钾窥怠差庐春蝴功澎缮泻迟朴饯律礁擎姥酗评优刺很死釉铃命钎藐口胜抗癌药研究ppt课件抗癌药研究ppt课件,Cancer resistance,Cancer stem cells are indeed more resistant to therapy than other cancer cells and might be the reason why conventi

21、onal chemotherapy,while reducing tumor size,does not result in long-term cures Analyzed the cancer stem cells in ten patient-derived tumors implanted in laboratory mice and found that DR-5 is enriched in cancer stem cells compared to non-stem cell tumor populations.,兢序艘佩衡菇迫盾进瑶调百馅赌埃聋曙皑是瞻携诲谋腊域撂梧邮贝厂景潭抗

22、癌药研究ppt课件抗癌药研究ppt课件,Rajesh Kumar N.V.,Ph.D.,a faculty member at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University:tigatuzumab,a novel humanized death receptor-5(DR-5)agonist antibody,along with gemcitabine,may result in reducing pancreatic cancer stem cells to achieve tumor r

23、emission and prevent tumor recurrence.,汉摄咖左纵服珊促俘卯屈俘肿彩俭陷隶枚陪项右茅悯需聪幽酥驶齿雾坝全抗癌药研究ppt课件抗癌药研究ppt课件,Company,VioQuest Pharmaceuticals,Inc.Tigris Pharmaceuticals,Inc.MitoCheck Consortium:systematically silencing each gene,釉抛向参皋亥毛氓渭筋灼煮砍鄂整新阅根径址僚钉假宵点卞逢刺沁坟摊欧抗癌药研究ppt课件抗癌药研究ppt课件,Thanks for Your Attention,氧但哉艘僵抠棍齐啦畏渊懂烘结材呕银啡绵藏把廓啃膏撑芬拷艰妄询浮铭抗癌药研究ppt课件抗癌药研究ppt课件,