Module 1: The Kinome: Small Molecule Discovery and Pharmacology
This module will introduce protein kinases as exciting and productive targets for therapeutic modulation in major
disease areas, and will provide a context for later modules of the course. The major importance of protein phosphorylation
and protein kinase cascades in the intracellular regulation of many cell functions and signalling mechanisms
will be discussed. The human kinome will be explored in terms of families of sequence-related enzymes, followed
by a brief introduction to protein kinase structure and catalytic mechanisms. This leads to a discussion of protein
kinases as drugable targets, including some of the caveats, which are associated with this therapeutic class,
and the issue of cellular resistance to kinase inhibitors.
Instructor – Dr. Paul England
Chief Executive Officer
ProXara Biotechnology Ltd
37, Avenue Rd.,
St. Albans, Herts AL1 3PY, U.K.
E-mail: p.england@proxara.com
Telephone: +44 172 737 3761
Paul England received his B.Sc. and Ph.D. from the University of Bristol (UK), and after a post-doctoral position
with Prof. Edwin Krebs at the University of California, Davis from 1971-73, he returned to the University of
Bristol as a Lecturer in Biochemistry. His research specialty was the role of protein phosphorylation in the
control of muscle function. In 1985 he joined Smith, Kline & French R&D (subsequently SmithKline Beecham)
in the Drug Discovery division. From 1994-7 he was Vice President Molecular Screening Technologies, in which
role he established and managed SmithKline Beecham’s entire high-throughput screening activities and
enzymology worldwide. From 1998-2000 he was Senior Vice President Research at Aurora Biosciences Corp. in San
Diego, with responsibility for assay development and screening. He is currently Chief Executive Officer of
ProXara Biotechnology Ltd, a company specializing in cell-based drug discovery using high content screening
technologies.
Module 2: Cell based and Biochemical Assay Strategies for Kinase Screening and Profiling
This module will provide an overview of the various strategies for assaying kinase activity in both cell-free
and cell-based contexts, with emphasis on the need for complementary use of both biochemical and cellular assays.
A variety of technologies will be reviewed where generic and specific issues for biochemical assays will be
addressed, including selection of active kinase, peptide/protein substrate and full length vs. kinase domain
fragments for assays. Homogeneous vs. heterogeneous formats will be discussed, the importance of kinetics will
be addressed and the potential formats of bidning of assays will be reviewed. Technologies based on radioisotope,
fluorescence, absorption, luminescence, antibody free/dependent methods and coupled enzyme approaches will
be presented. The discussion of cell-based assays will begin with a review of criteria for choosing the cell
type(s) to be used and the importance of validating relevant and representative biological response. Technlogies
including measurement of protein phosphorylation in cells, ELISA, reporter gene and protein translocation readouts,
and high content screening will be reviewed. The module will conclude with a discussion of the use of all these
technologies to perform comprehensive kinase pathway profiling.
Instructor – Dr. Pirthipal Singh
Associate Principal Scientist
AstraZeneca
Merside, Alderley Park
Macclesfield, Cheshire SK10 4TG UK
Phone +44 (0) 1625 516 640
Fax: +44 (0) 1625 513 441
E-mail: pirthipal.singh@astrazeneca.com
Pirthipal Singh graduated from Leeds University in Biochemistry and started his career in industry, (December
1978), at the Alderley Park laboratories of ICI Pharmaceuticals (latterly Zeneca Pharmaceuticals and now AstraZeneca).
He has worked primarily in the area of biochemical assay development, for medium and high throughput screening,
where he has had a longstanding interest in the evaluation & implementation of ‘new’ technologies
and assay design, into Drug Discovery programs.
Instructor – Dr. Len Pagliaro
VP Business Development
BioImage A/S
Moerkhoej Bygade 28
2860 Soeborg, DENMARK
len.pagliaro@bioimage.com
+45 44 43 75 25 (office)
Len Pagliaro is Vice-President, Business Development at BioImage A/S in Copenhagen, Denmark. From 2000-2003,
he served in line and project management roles at BioImage, most recently as VP, Discovery Projects. Prior
to joining BioImage, he was Principal Scientist at Cerep, Inc., where he led development of pharmaceutical
profiling assays and served as study director. He received his Ph.D. from Wesleyan University, completed postdoctoral
training at Carnegie Mellon University, and served on the Bioengineering and Laboratory Medicine faculties
at the University of Washington School of Medicine from 1990-1997. He is a member of the editorial board of
the Journal of Biomolecular Screening and the scientific advisory board of Acucela Inc.
Module 3: Chemical Library Development and Lead Optimization of Kinase Inhibitors
This module will describe the main challenges facing the development of kinase inhibitors including solubility,
novelty and selectivity. The main focus of the discussion, however, will be on selectivity: how it is achieved
and how it is assessed. Following a brief overview of the challenges, the different modes of kinase inhibition,
including ATP competitive, allosteric, non-competitive and substrate competitive, will be closely examined.
For this portion of the discussion particular emphasis will be placed on relating SAR to the kinase structure.
Finally, a variety of techniques for assessing kinase selectivity will be presented, and some of the open issues
as to the extent of selectivity needed will be explored.
Instructor – Dr. David Diller
Research Manager
Pharmacopeia Drug Discovery Inc.
ddiller@pcop.com
3000 East Park Blvd, Cranbury NJ, 08512
CN5350, Princeton, NJ 08520
609-452-3783
David Diller received his Ph.D. in mathematics from Northwestern with a specialty in partial differential equations
in 1996. Recognizing greener pastures, he accepted a Sloan Fellowship to move into an applied discipline. With
this fellowship, David spent 3 years as a post-doc in Wim Hol’s group at the University of Washington.
During this time, he was fortunate enough to be able to work on a wide range of problems including: modeling
protein crystallization experiments, interpreting electron density maps, and structure based drug design. David
spent the last 7 years at Pharmacopeia. Initially, he worked on developing high through put docking methods.
Ultimately, the attraction of applying these and other methods became too strong. Now David spends most of
his time thinking about how computational chemistry, molecular modeling and bioinformatics techniques can be
applied to design chemical libraries for families of targets such as kinases, GPCRs etc. and how this information
can be used to downstream in the drug discovery process to greater benefit.
Module 4: Methods and Issues in Selecting Protein Kinase Targets
Module 5: Development and Clinical Trials for Kinase Targeted Compounds
· Actual examples of specific kinase inhibitors used clinically
· Targeted molecules (currently) vs the non-selective cytotoxic therapies (of year's past)
· Exactly how are successful clinical kinase inhibitors developed?
· What are the challenges to developing a successful candidate drug?
· How to select the appropriate patient population
· Choosing the dose
·
The Tarceva vs Iressa "pass-fail" system (lessons learned)
· Biomarkers: hope versus hype
· The Gleevec story
· Endpoints with and without tumor shrinkage
· Unexpected toxicities (ex. Herceptin cardiotoxicity) Instructor - Dr Kapil Dhingra
Roche Clinical
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