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A knowledge-rich approach to drug discovery

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  • 1. A knowledge-rich approach to drug discovery Finding of potential drug against glioblastoma © 2009 Ariadne. All Rights Reserved. Ekaterina Kotelnikova PhD | 07.23.2009
  • 2. Ariadne Pathway Studio ChemEffect: Compound protein targets, and molecular, cellular and physiological effects Knowledge databases: - ResNet® Mammalian - ChemEffect® Knowledge Databases MedScan® Library Pathway Building Gene expression analysis
  • 3. ChemEffect Toxicities Cell processes Expression, Binding, Regulation Conditions Regulation Relation Description Count Small molecule -> Conditions/CellProcess effects (+/-) Physiological effects, generally indirect. Toxicities, including positive and negative effects ~340,000 Small molecule– protein binding Protein – small molecule bindings 17,186 Small molecule –> Protein inhibitor/activator Direct drug effects on protein targets 46,748 Small molecule -> protein expression Regulation of protein expression by drugs 63,296 Small molecule -> Protein effects (+/-) Indirect effects of small molecules on proteins ~150,000 Small molecule metabolization Proteins/Enzymes metabolizing drug 6,541 Small molecule transport Proteins/Enzymes involved in drug transport 1,757
  • 4. Entities in ChemEffect Proteins: 9,058 Small molecules: 20,718 Diseases/Toxicities: 4,479 Cellular processes: 1,866 Protein classes/Enzymes: 2,339
  • 5. Workflow Disease: Glioblastoma Canonical pathway Expression profile Significant regulators (Cyr61 and NOV) Intersection: Fulvestrant Compounds known to affect proteins in the pathway Compounds known to inhibit Cyr61/NOV
  • 6. Glioblastoma quick facts Astrocytoma Survival: 5-10yrs Loci: p53, PDGF/R Pathobiology: moderate proliferation, invasion Anaplastic astrocytoma Survival: 2-3yrs Loci: CDK4/6, Rb, 19q/11q loss Pathobiology: proliferation, invasion, angiogenesis Glioblastoma Survival: 9-12mos Loci: PTEN, 10q loss, EGFR, Cyclin D, mdm2, Bcl2L12 Pathobiology: proliferation, invasion, angiogenesis,necrosis Furnari , et al; Genes Dev. 2007 21: 2683-2710
    • Most vascularized cancer
    • relentless malignant progression
    • Apoptosis - resistant
  • 7. Glioblastoma pathway © 2009 Ariadne. All Rights Reserved.
    • Pathway was built from few latest reviews
    • Main signaling pathways (PKC, NFkB, MAPK, mTOR, beta-Catenin) and other key proteins were identified
    • These signaling pathways and proteins were found in the PathwayStudio® database
    • They have been combined into one pathway
  • 8. Glioblastoma Treatment © 2009 Ariadne. All Rights Reserved.
    • No effective treatment yet
    • Current treatment: radiotherapy & traditional chemotherapy
    • Inhibitors of glioblastoma pathway are in various stages of clinical trials with mixed outcome
    Wong , et al; J Clin. Neurosci. 2007 21: 301-308 Tuettenberg , et al; Crit. Rev. in Onc. Hemat. 2006 59: 181-193 Current opinion: targeting multiple proteins may be more efficient Becavizumab Cetuximab Imatinib ZD6474 Pazopanib Gefitinib Erlotinib Lapatinib Enzastaurin Tamoxifen Tipifarnib Lonafarnib Sorafenib Bortezomib Sirolimus Everolimus Temsirolimus
  • 9. ChemEffect drugs against Glioblastoma pathway, targeting multiple proteins
    • 750+ compounds in ChemEffect down-regulating pathway
    • Top 40 targeting multiple proteins
    • Many of them haven’t been tried against glioblastoma?
  • 10. Fulvestrant: effective against Glioblastoma?
    • Estrogen receptor antagonist
    • Used in treatment of hormone receptor-positive metastatic breast cancer
    • Tamoxifen, another ER antagonist and PKC inhibitor is partially effective against glioblastoma
    Couldwell , et al; Clin. Cancer Res.. 1996; 2: 619-622
  • 11. Workflow Disease: Glioblastoma Canonical pathway Expression profile Significant regulators (Cyr61 and NOV) Intersection: Fulvestrant Compounds known to affect proteins in the pathway Compounds known to inhibit Cyr61/NOV
  • 12. Glioblastoma Gene Expression Analysis Workflow GE: Glioblastoma vs. Normal Differential expression profile Sub-Network Enrichment Analysis High-scoring components
    • PathwayStudio 6 Sub-Network Enrichment Analysis Tool
    • Statistical test, similar to Broad Institute Gene Set Enrichment Analysis (GSEA)
    • Sub-networks are built dynamically around all proteins and represent their expression targets in the database
    • Identify key regulators of differentially expressed genes
  • 13. Result: Cyr61 and NOV: Novel therapeutic targets ? © 2009 Ariadne. All Rights Reserved. Regulated by estrogen Inhibit apoptosis Act through integrins Activate cancer pathways: AKT, FAK and beta-Catenin Matricellular proteins, interact with matrix proteins, growth factors and their receptors Regulate angiogenesis and cell migration Regulate ECM remodeling Regulated by HIF1A, a main regulator of angiogenesis
  • 14. Cyr 61 and NOV: ChemEffect activators and inhibitors Inhibitors: potential drugs? Activators: steroids
  • 15. Fulvestrant: effective against Glioblastoma?
    • Estrogen receptor antagonist
    • Used in treatment of hormone receptor-positive metastatic breast cancer
    • Tamoxifen, another ER antagonist and PKC inhibitor is partially effective against glioblastoma
    Couldwell , et al; Clin. Cancer Res.. 1996; 2: 619-622
  • 16. Summary
      • Identify compounds affecting target proteins or pathways
      • Identify targets affected by similar compounds
      • Survey side-effects associated with compounds
      • Use experimental data to build drug action hypothesis and identify potential drug targets
      • Identify potential alternative drug indications
    Disease: Glioblastoma Canonical pathway Expression profile Significant regulators (Cyr61 and NOV) Intersection: Fulvestrant Compounds known to affect proteins in the pathway Compounds known to inhibit Cyr61/NOV
  • 17. Acknowledgements
      • Nikolai Daraselia, PhD
  • 18. Glioblastoma vs. Normal values distribution Left shift
  • 19. Look at potential side effects