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 discoveryIdentification and validation of targetEmerging targetsDrug design and HTSIdentification and validation of targetGenomics analytic technology: microarray analysis, high-throught RNAi, Ambion, In

7、c. 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 targetsOncogenes and apoptosis-inhibiting genes, mainly

8、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 metastasisthe Moffitt Cancer Center Drug Discovery P

9、rogram at the University of South FloridaUniversity 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 pathwayvmacrophage

10、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 ScreeningvX-r

11、ay 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 contrib

12、ute 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 “l(fā)ead optimizati

13、on 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 (LC-MS):

14、 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 vPredict po

15、ssible 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 targets, bioch

16、emical 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: vCan not dis

17、cover a small molecule that restores protein functionvPharmacologic effect of the compound at a cellular or organism level maybe influencedvSolution :Again doing Cell-based assaysv 1. drugs pharmacologic effects at the cellular levelv 2. discovery new targetsv Target-based and cell-based screening f

18、or new anticancer drugsv 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 i