抗癌药研究

nullnull Anti-cancer Drug Discovery and Development Outline Outline Anti-cancer drug discovery process The approach to anti-cancer drug discovery Identification and validation of target Computer aided drug design Small Moleculars screening through HTS Metabolic and Physicochemical Profiling of drug Cancer resistanceAnti-cancer drug discovery processAnti-cancer drug discovery processModern molecular biology and genomics/proteomics to identify and validate new therapeutic targets Combinatorial chemistry for the efficient generation of structural 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 discover lead drugs High-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 proteomicsThe approach to anti-cancer drug discoveryThe approach to anti-cancer drug discovery cell-based screening Targeting the specific molecular lesions Cell-based screeningCell-based screening1.cell-based cytotoxicity assays: random high-throughput screening of synthetic compounds and natural products, based on anti-proliferative 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 lineTarget-based screening for anti-cancer drug discoveryTarget-based screening for anti-cancer drug discovery Identification and validation of target Emerging targets Drug design and HTS Identification and validation of targetIdentification and validation of target Genomics analytic technology: microarray analysis, high-throught RNAi, Ambion, Inc. Cenix BioScience Proteomics analytic technology:affinity chromatography and mass spectrometry X-omics analytic technology Epigenomics (DNA methylation and histone deacelylation), Cytomics, Metabolomics, Interatomics, Bioinformomics Emerging targetsEmerging targets Oncogenes 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 metastasis the Moffitt Cancer Center Drug Discovery Program at the University of South Florida University of Illinois:FoxM1 Inhibitors are Anticancer Drugs that Induce Cell Death nulltargeting Wnt signaling miRNAs, Hedgehog signaling the Notch pathway metabolic pathways the immune system specific inflammatory mediators TGFβ signaling pathway macrophage stimulating protein (MSP) and its receptor Ron Rho GTPase signaling network the IGF signaling network Apoptosis and cell cycle: Ras, a GTPase , Raf/Mek, Erk1/2, PI3K/Akt , p53 , CDK4 , CDK4 activator cyclin D1 , CDK4 inhibitor p16 , Bcl-2 genes Structure-Based Drug Design & Virtual ScreeningStructure-Based Drug Design & Virtual ScreeningX-ray crystal structures and/or homology models Virtual screening (VS) technologies: computationally “dock” small molecules into the active sites of our molecular targets Visualize and probe molecular interactions in 3D using advanced computational graphics systems to understand the forces that contribute to enhanced binding null High-Speed Analoging: parallel synthesis and high-throughput purification techniques coupled with computational chemistry 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 processes strong hardware platform, state-of-the-art software suites High-throughput Screening (HTS) High-throughput 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” for confirmation testing within 24 hours Metabolic and Physicochemical Profiling Metabolic and Physicochemical Profiling Solubility and permeability, how well a drug is absorbed Metabolization by subcellular liver microsomes Predict possible drug-drug interactions, testing their inhibitory effect on cytochrome P450 enzymes Identify those compounds that have the greatest chance of succeeding as drugs Molecular Imaging, luminescence and fluorescence imaging, visualize and quantitate non-invasively specific molecular targets, biochemical pathways and physiological effects of novel drug candidates in vivo Success molecularly targeted drugsSuccess molecularly targeted drugsAll-trans-retinoic acid for acute promyelocytic leukemia imatinib (STI-571) for chronic myelogenous leukemia target-based screening for anti-cancer drug discovery target-based screening for anti-cancer drug discovery Shortcomings: Can not discover a small molecule that restores protein function Pharmacologic effect of the compound at a cellular or organism level maybe influenced Solution :Again doing Cell-based assays 1. drug’s pharmacologic effects at the cellular level 2. discovery new targets Target-based and cell-based screening for new anticancer drugs in the molecular targeting era are complementary methods Cancer resistanceCancer resistanceCancer stem cells are indeed more resistant to therapy than other cancer cells and might be the reason why conventional 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. nullRajesh 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 remission and prevent tumor recurrence. CompanyCompanyVioQuest Pharmaceuticals, Inc. Tigris Pharmaceuticals, Inc. MitoCheck Consortium: systematically silencing each gene null Thanks for Your Attention