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The regulation of cell behaviour by chemical signals, such as hormones and growth factors, usually involves interactions between a broad range of extracellular stimuli with their respective cell surface receptors. Such interactions result in a diverse array of responses including cell proliferation, differentiation, gene transcription, metabolism, motility and apoptosis. Disruption or over-stimulation of these signal transduction pathways can ultimately lead to diseases such as cancer and diabetes, as well as neurodegenerative, inflammatory and immune disorders. Hence, the importance of understanding these pathways cannot be underestimated and their potential as therapeutic targets is overwhelming.

SMi has identified this as a key time to provide updates on developments in this industry. The conference will aim to evaluate the recent focus on signal transduction inhibitors as therapeutics for cancer, as well for diseases of the eye, kidney and immune system, which are showing signs of increased efficacy and reduced side effects compared to many existing drugs. Target identification and validation, drug screening methods and current advancements in therapeutic design and development are some of the areas that will be considered in order to lead signal transduction therapeutics into the future.

Conference programme

8:30 Registration and Coffee

9:00 Chairman's Opening Remarks

Prof Stephen Hill

Prof Stephen Hill, Director, Institute of Cell Signalling, Professor, Molecular Pharmacology, University of Nottingham

9:10 NOVEL LEAD GENERATION USING RAPID PROTEIN/LIGAND CRYSTALLOGRAPHY

Dr Neil Thompson

Dr Neil Thompson, Vice President, Biology, Astex Technology

  • The use of X-ray crystallography as a method for screening low-affinity compounds
  • Generating libraries of molecular fragments
  • Rapid optimisation of initial leads using structure-based design
  • Exploiting systems-based research to target multiple members of a protein family
  • 9:40 HIGH-THROUGHPUT SCREENING OF COMBINATORIAL LIBRARIES APPLIED TO SIGNAL TRANSDUCTION TARGETS

    Dr Douglas Auld

    Dr Douglas Auld, Senior Group Leader, Pharmacopeia

  • Overview of core technology
  • Target class success
  • UHTS of a GPCR
  • Intracellular targeting
  • 10:20 APPROACHES TO DRUG DISCOVERY AT GPCRS

    Dr Nigel Beeley

    Dr Nigel Beeley, Vice President & Chief Chemical Officer, Arena Pharmaceuticals

  • Drug discovery at G-protein coupled receptors (GPCRs)
  • Application of CARTTM (Constitutively Activated Receptor Technology) to GPCRs
  • Project genesis: a massively parallel program to complete drug discovery at GPCRs
  • Functional genomics with particular reference to Affymetrix GenechipTM technology
  • Combination of Melanophore technology and CARTTM for high throughput screening
  • Tracking data with the Arena database

    Some recent results from the above efforts

  • 11:00 Morning Coffee

    11:20 CELL-BASED ASSAYS FOR SCREENING IN DRUG DISCOVERY

    Dr Ole Thastrup

    Dr Ole Thastrup, Chief Technology Officer, BioImage

  • Adopting technologies amenable to miniaturisation and rapid assay development
  • Increasing use of cells for high-throughput and ultra high-throughput screens
  • Using a suitable format of cell based assays to identify the site of action from an intact cellular environment
  • Using better characterised cell lines: using human cells where possible
  • Allowing hundreds of enzymes to be considered simultaneously
  • 12:00 FUNCTIONAL GENE-BASED ASSAY PLATFORM

    Dr Fabrice Piu

    Dr Fabrice Piu, Head, Signal Transduction Group, Acadia

  • Chemical genomics vs target validation
  • Cell-based assays and genomic targets: limitations?
  • Pharmacological capabilities of functional assays
  • R-SATTM and its broad applicability
  • Identifying hits for GPCRs and nuclear receptors
  • 12:40 Lunch

    13:40 ADDRESSING THE CHALLENGE OF TARGET VALIDATION

    Dr Frank Mercurio

    Dr Frank Mercurio, Director, Cell Signalling & Target Discovery, Celgene

  • Kinases and E3 ubiquitin ligases as key therapeutic targets to modulate signal transduction pathways
  • Multiple dimensions of target-specific information: predictive cell-based assays, focused proteomics, gene array analysis, kinase activity profiling
  • Feasibility of identifying small molecules that modulate protein-protein interactions
  • Characterising and prioritising hits for further chemistry and validation via biological models
  • Generating more biologically relevant information: improving the quality of chemistry
  • The future: monitoring complex formation and panels of screens
  • 14:20 THE STRUCTURE AND FUNCTION OF PDK1

    Dr Dario Alessi

    Dr Dario Alessi, Principal Investigator, MRC Protein Phosphorylation Unit, University of Dundee

  • AKT/PKB
  • P13 kinase
  • Cell growth
  • P70S6 kinase
  • PH domains
  • 15:00 LYN INHIBITION INDUCES REGRESSION OF HUMAN PROSTATE CANCER XENOGRAFTS

    Dr Isaiah Wexler

    Dr Isaiah Wexler, Medical Research Director, Keryx Biopharmaceuticals

    15:40 Afternoon Tea

    16:00 TARGETING VEGF RECEPTORS FOR ANGIOGENESIS THERAPIES

    Dr Jan Rosenbaum

    Dr Jan Rosenbaum, Principal Scientist, Cardiovascular Research, Procter & Gamble

  • The VEGF receptors as validated targets for angiogenic therapies
  • Introduction to VEGF receptors and downstream signalling pathways
  • Differences between the VEGFR-1 and VEGFR-2 receptor tyrosine kinases
  • The role of neuropilin-1 as a VEGF165 co-receptor
  • Similar signalling endpoints do not always imply similar mechanistic inputs
  • Implications for interpretation of results from drug screening assays
  • 16:40 CALCIUM SIGNALLING VIA THE NEURONAL CALCIUM SENSOR-1

    Prof Patrick Nef

    Prof Patrick Nef, Vice Director, Head of Psychiatry, F. Hoffman-La Roche

  • A new pathway to cure cognitive declines associated with neurodegenerative diseases such as Alzheimer’s, schizophrenia or normal ageing.
  • 17:20 Chairman’s Closing Remarks and Close of Day One

    8:30 Re-registration and Coffee

    9:00 Chairman's Opening Remarks

    Dr Bert Klebl

    Dr Bert Klebl, Vice President, Research, Axxima

    9:10 SELECTING PROTEIN TYROSINE PHOSPHATASES (PTPS) AS SIGNALLING DRUG TARGETS

    Dr Robert Hooft

    Dr Robert Hooft, Senior Scientist & Project Leader, Tyrosine Phosphatase Targets, Serono

  • Rationale and prospects for PTPs as drug targets
  • The PTP1B/ diabetes paradigm; in vivo activity of PTP1B inhibitors
  • Other potential PTP drug targets and validation issues
  • Discovery of PTBs with substrate specificity for the GH-activated GHR
  • 9:40 TARGETING CHEMOKINE SIGNALLING

    Dr Christian Rommel

    Dr Christian Rommel, Head, Signal Transduction, Serono

  • Chemokine signalling and autoimmune/inflammatory diseases
  • Pathway mapping by genetic inactivation and chemical inhibition of chemokine signal transduction
  • Post-genomic target validation by chemical genetics
  • Signalling specificity: insights into complex signalling networks and kinase isoform exclusivity
  • Development of P13K and MAPK isoform selective small molecule inhibitors
  • Fishing for novel targets by phospholipid proteomics
  • 10:20 INHIBITORS OF P13K PATHWAY COMPONENTS AS ANTI-CANCER AGENTS

    Dr Jasbinder Sanghera

    Dr Jasbinder Sanghera, Chief Scientific Officer, Kinetek

  • Blocking metastasis
  • Triggering selective apoptosis
  • Modulating the cell cycle
  • Efficacy vs. toxicity
  • 11:00 Morning Coffee

    11:20 NEW TARGETS FOR ANTI-CANCER THERAPY

    Dr Peter Traxler

    Dr Peter Traxler, Senior Scientist, Research Manager, Novartis

  • From genome to new kinase targets
  • The use of a pharmacophore model of the ATP-binding site for rational drug design
  • The long way from research into clinics
  • Is there a selectivity issue?
  • PKI166: a dual EGFR/ErbB-2 inhibitor
  • The Gleevec story (ST1571): treatment of CML, GIST and solid tumours
  • 12:00 STRUCTURAL GENOMICS OF THE HUMAN KINASE FAMILY

    Dr Jacek Nowakowski

    Dr Jacek Nowakowski, Project Leader, Syrrx

  • Syrrx’s expression and purification system
  • High-throughput crystallography platform
  • Novel kinase structures involved in human cancer
  • 12:40 Lunch

    14:00 LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE BETA (LPAATb)

    Dr Jack Singer

    Dr Jack Singer, Research Programme Chairman & Executive Vice President, Cell Therapeutics

  • Highly expressed in many common tumours and tumour stroma compared to normal tissues
  • Abrogation of activity by RNAi or isoform specific small molecule inhibitors induce apoptosis in a broad variety of tumour cell lines
  • LPAATb increases actions of transforming ras/raf
  • Ras transformation increases activity of LPAATb
  • Suppression of activity by isoform specific inhibitors (IC50’s<100nM) prevent raf translocation, MAPK activation and translocation and activation of AKT/mTOR in VEGF or angiotensin-stimulate endothelial cells
  • LPAATb inhibitors are well tolerated and have anti-tumour activity in murine tumour models
  • 14:40 HSP90 MODULATORS

    Dr Francis Burrows

    Dr Francis Burrows, Director, Biology Research, Conforma Therapeutics

  • HSP90 is a molecular chaperone required for the activity of a range of signal transduction regulators
  • HSP90 clients are required for mitogenesis, cell cycle control and survival signalling in malignant cells
  • Ansamycin HSP90 modulators bind to an atypical ATP binding site in the N-terminal domain of the protein
  • HSP90 modulators induce a Rb-dependent G1 arrest followed by apoptosis in diverse tumour cells
  • Conforma’s 2nd generation ansamycins are potent HSP90 inhibitors with improved pharmaceutical properties
  • HSP90 modulators cause tumour regression alone or in combination with chemotherapeutic drugs
  • 15:20 Afternoon Tea

    15:40 BLOCKING RECEPTOR/LIGAND INTERACTIONS BY THERAPEUTIC VACCINATION

    Dr Martin Bachmann

    Dr Martin Bachmann, Chief Scientific Officer, Cytos Biotechnology

  • Patient compliance: a major problem for the treatment of chronic diseases
  • Repetitive arrays of self-antigens as therapeutic vaccines
  • Long-lived immune responses induced by therapeutic vaccines may overcome patient compliance hurdle
  • Antibody responses can selectively block the action of protein molecules
  • Therapeutic vaccines: can they replace monoclonal antibodies?
  • 16:20 Chairman's Closing Remarks and Close of Conference

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    Workshops

    Using High-Throughput Cell-Based Systems For Studying Signal Transduction
    Workshop

    Using High-Throughput Cell-Based Systems For Studying Signal Transduction

    The Hatton, at etc. venues
    4th October 2002
    London, United Kingdom

    The Hatton, at etc. venues

    51/53 Hatton Garden
    London EC1N 8HN
    United Kingdom

    The Hatton, at etc. venues

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