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Scheduled
immediately following CHI's GPCRs:
From Orphan to Blockbuster, June 7-8, 2004, Boston,
Massachusetts
Day 2
Thursday, June 10
Drug Development:
Design
8:15 Breakfast Technology
Workshop
Variation Detection Platform at Agencourt Bioscience |
Sponsored
By: |
Dr. Krista Steger, Marketing Manager, Marketing
Agencourt Bioscience |
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9:00 Comments by Session
Chairperson
Dr. Chris J. Vlahos, Head, Atherosclerosis-Vascular Wall
Drug Discovery Team, Cardiovascular Research, Lilly Research
Laboratories
9:10 Application of
Knowledge Constraints to Virtual Screening for Kinase
Inhibitors: Ligand and Receptor Based Strategies
Dr. Claudio Chuaqui, Senior Scientist, Research
Informatics, Biogen Idec
We have recently reported SIFt (structural interaction
fingerprint), a method for representing and analyzing 3D
protein-ligand binding interactions. Key to this approach is the
generation of an interaction fingerprint that translates 3D
structural binding information from a protein-ligand complex
into a one-dimensional binary string. We have applied SIFt to
analyze approximately 90 known X-ray crystal structures of
protein kinase-inhibitor complexes obtained from the Protein
Databank. The analysis revealed striking similarities and
diversity between their small molecule binding interactions.
SIFt can be used as an effective knowledge based filter during
receptor-based virtual screening to select molecules with
desirable binding mode(s) and/or desirable interaction patterns
with the kinase target. We have also applied knowledge
constraints to ligand-based virtual screening resulting in the
discovery of a potent inhibitor of the Type I TGF Receptor
Kinase (TRI).
9:40 Chemometrical Analysis
of Ephrin-Eph Kinase Interactions using GRID/CPCA Approach
Dr. Eugene Myshkin, Rammelkamp Center for Research,
MetroHealth Campus, Case Western Reserve School of Medicine
Eph kinases and their ephrin ligands play crucial role in
cell migration and cell proliferation processes like
angiogenesis, neurogenesis and carcinogenesis, and as such
represent a potential target for drug design. We have analyzed
the binding sites of 13 Eph kinases and 8 ephrins using GRID/CPCA
approach and identified structural features required for
interaction with Eph kinases. Virtual screening of Available
Chemical Directory yielded a small molecule that acts as an
agonist of EphA2 kinase and has drug like properties.
10:10 Strategies for the
Cloning, Expression and Purification of Enzymatically Active
Protein Kinases from Insect Cells.
Dr. Simon E Plyte, Head Biotechnology Laboratory,
Pharmacia - Gruppo Pfizer Inc, Nerviano, Italy
The provision of high quality protein reagents for assay
development is fundamental to the generation of robust and valid
biochemical assays and in the identification and optimization of
superior lead compounds. One of the key points is to be able to
reproducibly generate large quantities of pure enzymes having
measurable activity sufficient to develop validated assays. We
have adopted a systematic approach to the expression and
purification of a large panel of protein kinases from insect
cells with a focus on resolving the problems of solubility and
enzyme activity
10:40 Poster and Exhibit
Viewing, Coffee Break
Applications
11:10 Comments by Session
Chairperson
Dr. Chris J. Vlahos
11:15 Development of Non-ATP
Competitive MEK Inhibitors
Dr. David Dudley, Inflammation Molecular Sciences, Pfizer
Global Research & Development
Use of the non-ATP competitive MEK inhibitors PD98059 and PD
184352 has greatly facilitated insight into the biological role
of MAP kinase signaling. This talk will highlight our experience
with these compounds from early screening to structural studies
to the clinical setting.
11:45 Rho Kinase Inhibitors
as Potential Therapeutic Agents for Cardiovascular Diseases
Dr. Erding Hu, Department of Vascular Biology and
Medicinal, GlaxoSmithKline Pharmaceuticals
RhoA and Rho-kinase (ROCK) participate in diverse cellular
signaling functions such as smooth muscle contraction,
cytoskeleton rearrangement and cell migration and proliferation.
In smooth muscle, ROCK plays an important role in calcium
sensitization, an event that controls vascular vessel tone.
Recent studies using ROCK inhibitors along with cellular and
molecular biology techniques have revealed a pivotal role of
this enzyme in many other aspects of cardiovascular function. I
will briefly review our current understanding of Rho/ROCK
signaling pathways and discuss the use of ROCK inhibitors as
therapeutic agents for cardiovascular disease diseases ranging
from hypertension to atherosclerosis.
12:15 The Discovery and
Development of a Novel Class of Mast Cell Activation Inhibitors
for Allergy and Asthma
Dr. Esteban Masuda, Director, Immunology, Rigel Pharmaceuticals
Summary Unavailable at Printing
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12:45 Luncheon Technology
Workshops
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Sponsored
by:
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Metal ion mediated polymer superquenching for highly sensitive detection of protein kinase and phosphatase activity.
Dr. Frauke H. Rininsland, QTL Biosystems
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2:00 Comments by Session
Chairperson
Dr. Stephen K. Burley, Structural GenomiX, Inc.
2:10 Cancer Drug Discovery
Involving Key Protein Kinases
Dr. William Shakespeare, Drug Discovery, ARIAD
Pharmaceuticals
Summary Unavailable at Printing
2:40 Targeting Protein
Kinases in Cancer Therapy
Dr. Doriano Fabbro, Novartis Institutes of Biomedical
Research, Oncology Research, Basel
Gain of function (GOF) mutations of PDGFR is in part
responsible for the hyper-eosinophilic syndrome (HES), chronic
myelomonocytic leukaemia (CMML) as well as a subset of
gastrointestinal tumors (GIST) which are sensitive to imatinib
treatment while GOFs in the Flt-3 receptor are a poor prognostic
factor for a subset of patients with acute myeloblastic leukemia
(AML). In AML, midostaurin has shown to effectively inhibit the
effects mediated by the GOF mutations in the Flt-3 gene in
vitro, in vivo and in the clinic indicating the utility of this
agent in the treatment of AML. As midostaurin has also activity
against the PDGFR and Kit, it may be used as an alternative
agent in diseases where these two protein tyrosine kinases have
become resistant to imatinib treatment due to mutation in the
kinase domain. Taken together, these novel treatment modalities
have validated the clinical utility of protein kinase inhibitors
as a therapeutic agent in GIST, HES, CMML, CML and AML. The
potential and limitations of these therapeutic approaches will
be discussed.
3:10 Selective Combinations
of Anticancer Agents: Toward Novel Use of Kinase Inhibitors
Dr. Mikhail V. Blagosklonny, Associate Professor of
Medicine, Brander Cancer Research Institute, New York Medical
College; Editor-in-Chief, Cell Cycle
This presentation discusses a potential use of kinase
inhibitors, including Iressa, to modulate cycle-dependent and
apoptosis-inducing chemotherapies. In the absence of a magic
bullet, selective anticancer effect still can be achieved by
hitting at least two matching targets. This approach may
radically change the path of drug discovery and cancer therapy.
3:40 Poster and Exhibit
Viewing, Refreshment Break
4:10
The Role of The Juxtamembrane Domain in FLT3
Autoinhibition and its Implications in Acute Myelogenous
Leukemia
Dr. Kumkum Saxena, Staff Investigator, Vertex Pharmaceuticals
FLT3 is a type-III receptor tyrosine kinase that plays an
essential role in the normal development of the stem cells and
the immune system. Two classes of activating mutations in FLT3
have been identified in patients with acute myelogenous leukemia
(AML). These are point mutations in the activation loop of the
kinase domain and internal tandem duplication (ITD) sequences in
the juxtamembrane (JM) domain. To further understand the nature
of FLT3 regulation, we have determined the crystal structure of
the autoinhibited form of FLT3 that includes the complete JM
domain. The structure of FLT3 provides direct insight into the
mechanism by which the JM domain exerts its autoinhibitory
effect on the catalytic activity of the kinase domain and the
role of the ITD in the constitutive activation of FLT3 in AML
patients.
4:40 Structure-guided Drug
Discovery for Protein Kinases using Fragment-based Lead
Identification/Lead Optimization
Dr.Sean Buchanan, Senior Director, Bioinformatics Structural GenomiX, Inc.
Applications of an integrated process that combines
high-throughput X-ray crystallography with a fragment-based
approach to parallel lead identification/lead optimization for
protein kinases will be presented. Crystallographic screening is
used to detect, visualize, and identify small, synthetically
facile fragments/scaffolds (MW 150-200) bound to the target
protein. Initial lead optimization involves using knowledge of
the co-crystal structure of the target-fragment complex and
advanced computational chemistry tools to guide high-throughput
organic synthesis of small, focused linear (one-dimensional)
libraries, which are evaluated with in vitro biochemical assays
and co-crystallography. Thereafter, optimal variations at each
point of chemical diversity are combined to synthesize focused
combinatorial (two- or three-dimensional) libraries that are
again examined with co-crystallography, cellular assays, and
initial DMPK and toxicity studies.
5:10 Close of Conference
Call for Sponsors and Exhibitors
Showcase your company's expertise, brand your solutions and
develop revenue opportunities with qualified decision-makers by
becoming an exhibitor or sponsor at GPCRs and Kinases.
Sponsorship opportunities include: technology workshop
presentations, poster competitions, refreshment breaks and
networking receptions just to name a few. We also have
high-visibility items such as conference padfolios and badge
lanyards, which will brand your company name and logo.
For more information on exhibiting
and sponsoring, please contact Arnie Wolfson at 781-972-5431, or
awolfson@healthtech.com
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