抗癌药研究ppt课件

1、 anti-cancer drug discovery and development outline vanti-cancer drug discovery processvthe approach to anti-cancer drug discoveryvidentification and validation of targetvcomputer aided drug design vsmall moleculars screening through htsvmetabolic and physicochemical profiling of drugvcancer resista

2、nceanti-cancer drug discovery processvmodern molecular biology and genomics/proteomics to identify and validate new therapeutic targetsvcombinatorial chemistry for the efficient generation of structural diversity and for rapid production of a library of structural analogues based on an identified le

3、ad compound and optimization, enhanced structural biology and molecular modeling techniques for rational drug design vrobotic high-throughput screening against structurally diverse chemical libraries to discover lead drugsvhigh-throughput pharmacokinetics assays, the use of surrogate end points to m

4、onitor pharmacodynamics throughout thediscovery and development process, particularly involving genomics (e.g., nucleic acid microassays) and proteomicsthe approach to anti-cancer drug discoveryvcell-based screeningvtargeting the specific molecular lesionscell-based screening1.cell-based cytotoxicit

5、y 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 transformatio

6、n nci: highly chemo-sensitive p388 leukemia cell linetarget-based screening for anti-cancer drug discoveryvidentification and validation of targetvemerging targetsvdrug design and htsidentification and validation of targetvgenomics analytic technology: microarray analysis, high-throught rnai, ambion

7、, inc. cenix bioscience vproteomics analytic technology:affinity chromatography and mass spectrometry vx-omics analytic technology epigenomics (dna methylation and histone deacelylation), cytomics, metabolomics, interatomics, bioinformomics emerging targetsvoncogenes and apoptosis-inhibiting genes,

8、mainly encoding proteins that are components of signal transduction pathways that regulate proliferation, differentiation, invasion/metastasis, angiogenesis and/or tumor apoptosis or cell death vtargets facilitating tumor-microenvironment interactions and metastasisvthe moffitt cancer center drug di

9、scovery program at the university of south floridavuniversity of illinois:foxm1 inhibitors are anticancer drugs that induce cell death vtargeting wnt signalingv mirnas, vhedgehog signalingvthe notch pathway vmetabolic pathwaysvthe immune systemvspecific inflammatory mediatorsvtgf signaling pathwayvm

10、acrophage stimulating protein (msp) and its receptor ronvrho gtpase signaling networkvthe igf signaling networkvapoptosis 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 screeni

11、ngvx-ray crystal structures and/or homology modelsvvirtual screening (vs) technologies: computationally “dock” small molecules into the active sites of our molecular targets vvisualize and probe molecular interactions in 3d using advanced computational graphics systems to understand the forces that

12、contribute to enhanced bindingvhigh-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 op

13、timization” drug discovery processesvstrong hardware platform, state-of-the-art software suiteshigh-throughput screening (hts) vincubating the target protein with mixtures of up to 500 compounds at a time.vsize exclusion chromatography (sec): seperating hits from unbound compounds vmass spectrometry

14、 (lc-ms): identifying the binders van industrial-scale robotic cherry-picker retrieves orders of screening “hits” for confirmation testing within 24 hoursmetabolic and physicochemical profiling vsolubility and permeability, how well a drug is absorbedvmetabolization by subcellular liver microsomes v

15、predict possible drug-drug interactions, testing their inhibitory effect on cytochrome p450 enzymesv identify those compounds that have the greatest chance of succeeding as drugsvmolecular imaging, luminescence and fluorescence imaging, visualize and quantitate non-invasively specific molecular targ

16、ets, biochemical pathways and physiological effects of novel drug candidates in vivo success molecularly targeted drugsvall-trans-retinoic acid for acute promyelocytic leukemiavimatinib (sti-571) for chronic myelogenous leukemia target-based screening for anti-cancer drug discovery vshortcomings: vc

17、an not discover a small molecule that restores protein functionvpharmacologic effect of the compound at a cellular or organism level maybe influencedvsolution :again doing cell-based assays 1. drugs pharmacologic effects at the cellular level 2. discovery new targets target-based and cell-based scre

18、ening for new anticancer drugs in the molecular targeting era are complementary methodscancer resistancevcancer 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 vanalyzed the cancer stem cells in ten patient-derived tumors