Report: Protein-Protein Interactions as Drug Targets: Focusing on Cell Circuitry TOC

Chapter 1 Executive Summary ................................................................... 1--1
Chapter 2 Introduction to Protein-Protein Interaction .......................... 2--1
Chapter 3 Cellular Events Requiring Protein-Protein Interaction......... 3--1
- Protein-Protein Interaction in Cancer Cells ......................................................... 3--5
- Protein-Protein Interaction in Insulin Pathway .................................................... 3--8
  - Alterations of Protein-Protein Interactions in Insulin Resistant States .......................3--10
Chapter 4 Targeting PPI: Market Outlook and Analysis ........................ 4--1
- Market Segmentation for Protein-Protein Interaction Therapeutics...................... 4--3
- Targeting PPI: Opportunities and Challenges ...................................................... 4--9
- Challenges to be Faced.....................................................................................4--12
- Peptides and Peptomimetic Molecules ..............................................................4--13
  - Phage Display Technology ................................................................................4--13
- Example of Peptides as PPI Inhibitors ...............................................................4--16
  - Peptides Targeting HIV-1 Protease Dimerization ...................................................4--16
  - Inhibitors of HSV Ribonuclease Reductase ...........................................................4--17
  - Inhibitors of p53/Hdm2 Interactions ..................................................................4--17
  - Small Molecule Inhibitors of PPI .........................................................................4--17
  - Inhibitors of the Interaction Between Bcl-xL or Bcl-2 and Bak-BH3 Domains ..............4--18
  - Inhibitors of Myc/Max Dimerization ....................................................................4--19
  - Inhibitors of MMP2/Integrin 疱・ interaction ......................................................4--20
  - Inhibitors of Binding of TNF-・to TNFRc1 .............................................................4--21
  - Inhibitors of LFA-1/ICAM-1 Interactions ..............................................................4--21
  - Inhibitors of iNOS Dimerization...........................................................................4--21
  - Agonists of the EPO Receptor............................................................................4--21
  - Agonist for Interaction between Human Growth Hormone and its
  - Mutated Receptor ...........................................................................................4--22
- Major Examples of PPI ....................................................................................4--22
  - Protein-Protein Interaction of MDM2 and p53......................................................4--22
- Protein-protein Interaction in Insulin Signaling Pathway .....................................4--23
  - Taxol: Inhibiting Protein-Protein Interaction...........................................................4--24
Chapter 5 Exploring Chemical Space to Develop PPI Inhibitors............ 5--1
- Fragment Based Discovery Approach (FBDA) ...................................................... 5--1
- Tethering Methodology ...................................................................................... 5--2
- Competitive Antagonist of IL-2 Receptor ............................................................ 5--4
- Competitive Antagonists of B7/CD28 ................................................................ 5--5
- Allosteric Inhibitors of Nerve Growth Factor ..................................................... 5--5
Chapter 6 Techniques to Study PPI ........................................................... 6--1
- The Yeast Two-hybrid System............................................................................. 6--1
- Yeast Two-Hybrid System .................................................................................. 6--2
- Detecting Successful Protein-Protein Interaction ............................................... 6--3
- Applications of Yeast Two-hybrid ........................................................................ 6--5
- Bioinformatics Tools for Studying PPI................................................................. 6--5
  - BIND - Biomolecular Interaction Network Database ............................................... 6--6
  - DIP - Database of Interacting Proteins ................................................................ 6--6
  - PIM - Protein Interaction Maps ........................................................................... 6--6
  - PathCalling Yeast Interaction Database ............................................................... 6--6
  - MINT - Molecular Interactions Database .............................................................. 6--7
  - GRID - The General Repository for Interaction Datasets ......................................... 6--7
  - InterPreTS - Protein interaction prediction through tertiary structure ....................... 6--7
  - STRING .......................................................................................................... 6--7
  - Mammalian protein-protein interaction database (PPI) ........................................... 6--7
  - InterDom - Database of Putative Interacting Protein Domains ................................. 6--8
  - IntAct Project ................................................................................................. 6--8
  - The Human Protein Interaction Database (HPID) ................................................... 6--8
  - ADVICE - Automated Detection and Validation of Interaction by Co-Evolution ............... 6--9
  - InterWeaver ................................................................................................... 6--9
  - PathBLAST - Alignment of Protein Interaction Networks ......................................... 6--9
  - ClusPro - Protein-protein Docking ....................................................................... 6--9
- Systems Utilized In Studying PPI.......................................................................6--10
  - Aclara ...........................................................................................................6--10
  - eTag・Assay System ......................................................................................6--10
  - AxCell Biosciences Corp. (Now a subsidiary of Cytogen) .........................................6--10
- Databases and Tools ........................................................................................6--12
  - ADVICE - Automated Detection and Validation of Interaction by Co-Evolution ..............6--12
  - eFsite ...........................................................................................................6--12
  - PDBjViewer ...................................................................................................6--12
  - IntAct Project ................................................................................................6--12
  - iPPI ...............................................................................................................6--13
  - IPPRED ..........................................................................................................6--13
  - PathBLAST ....................................................................................................6--14
  - PEDANT - Protein Extraction, Description, and Analysis Tool ..................................6--14
  - PDBSiteScan ..................................................................................................6--14
  - PDGcon - Contact Prediction Server ..................................................................6--14
  - PIVOT - Protein Interactions VisualizatiOn Tool .....................................................6--14
  - Protein-Protein Interaction Server ......................................................................6--14
  - SPIN-PP Server - Surface Properties of Interfaces -- Protein-Protein Interfaces ..........6--15
  - STRING - Search Tool for the Retrieval of Interacting Genes/Proteins ......................6--15
  - YETI - Yeast Exploration Tool Integrator................................................................6--15
- Web Guide for PPI............................................................................................6--16
  - Databases / Data Collections............................................................................6--16
  - Experimental Data ..........................................................................................6--16
Chapter 7 Expert Opinions .......................................................................... 7--1
- Robin Carr Ph.D., Astex Technology .................................................................. 7--1
- Stefan L蚶, Ph.D., Biacore International AB .................................................... 7--3
- James Wells, Ph.D., Sunesis Pharmaceuticals, Inc.............................................. 7--5
- Len Pagliaro, Ph.D., BioImage A/S..................................................................... 7--7
- Donny Strosberg, HYBRIGENICS ....................................................................... 7--9
- Mike Cardone, Merrimack Pharmaceuticals, Inc. ...............................................7--12
- Richard Chen, Ingenuity Systems ......................................................................7--14
- Peter van Dijken Ph.D., Pepscan Systems BV ....................................................7--16
- Kannan Gunasekaran, SAIC-Frederick, Inc. ........................................................7--17
Chapter 8 Company Profiles ....................................................................... 8--1
- CATEGORY 1 .................................................................................................... 8--2
- Astex Technology .............................................................................................. 8--2
- Cytogen Inc. ..................................................................................................... 8--5
- Cellzome AG ..................................................................................................... 8--7
- CATEGORY 2 ...................................................................................................8--11
- Aclara Biosciences Inc......................................................................................8--11
- Biacore International AB ..................................................................................8--14
- BioImage .........................................................................................................8--17
- Dualsystems Biotech AG ..................................................................................8--18
- Hybrigenics......................................................................................................8--20
- Prolexys Phamaceuticals Inc.............................................................................8--23
- Odyssey Thera, Inc...........................................................................................8--26
- Syrrx, Inc. .......................................................................................................8--28
- CATEGORY 3 ...................................................................................................8--31
- GPC Biotech AG ...............................................................................................8--31
- Hypromatrix, Inc..............................................................................................8--36
- Protana Inc. ....................................................................................................8--41
- Panomics, Inc. .................................................................................................8--43
- Pierce Biotechnology, Inc..................................................................................8--47
- Stratagene ......................................................................................................8--49
Chapter 9 References .................................................................................. 9--1
Appendix: PPI Patent Analysis .............................................................. Appx--1

Protein-Protein Interactions as Drug Targets: Focusing on Cell Circuitry

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