Your SlideShare is downloading. ×
A knowledge-rich approach to drug discovery
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

A knowledge-rich approach to drug discovery

193
views

Published on


0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
193
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. Ariadne Pathway Studio Knowledge Databases ChemEffect: Compound protein targets, and molecular, cellular and physiological effects MedScan® LibraryLibrary Knowledge databases: - ResNet® Mammalian - ChemEffect® Pathway Building Gene expression analysis
  • 3. © 2009 Ariadne. All Rights Reserved. ChemEffect 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 Toxicities Cell processes Expression, Binding, Regulation Conditions Regulation
  • 4. © 2009 Ariadne. All Rights Reserved. Entities in ChemEffect Proteins: 9,058 Small molecules: 20,718 Diseases/Toxicities: 4,479 Cellular processes: 1,866 Protein classes/Enzymes: 2,339
  • 5. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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 Becavizumab Cetuximab Imatinib ZD6474 Pazopanib Gefitinib Erlotinib Lapatinib Enzastaurin Tamoxifen Tipifarnib Lonafarnib Sorafenib Bortezomib Sirolimus Everolimus Temsirolimus Current opinion: targeting multiple proteins may be more efficient
  • 9. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. Cyr 61 and NOV: ChemEffect activators and inhibitors Inhibitors: potential drugs? Activators: steroids
  • 15. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. 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. © 2009 Ariadne. All Rights Reserved. Acknowledgements • Nikolai Daraselia, PhD
  • 18. © 2009 Ariadne. All Rights Reserved. Left shiftLeft shift Glioblastoma vs. Normal values distribution
  • 19. © 2009 Ariadne. All Rights Reserved. Look at potential side effects