Drug%20Discovery%20and%20Genomics

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Drug Discovery and Genomics

• How the Sequencing of the Human Genome and
  Related Developments has Impacted Drug Discovery

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Fortunes will be won and lost in the genome
grab. The race to secure the sequence patents
will be over in five Years. The World in 2001.
The New Economist on pharma- ceuticals.
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The Promise
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The Concern
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Bottom Line
The Human Genome Project and related technologies
has generated thousands of novel potential drug
targets. Validating those targets and their
drugability and generating therapeutic options
are now the rate limiting steps in drug
development.
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Topics

• What is Genomics ?
• What is the relationship between genes and
  disease?
• What are the steps in developing a drug?
• What impact has genomics had on the process of
  drug development?

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What is Genomics ?

• Study of information stored in the genome
• structural and functional information
• Structural genomics the sequence
• Information is encoded linearly and digitally in
  four coding molecules-bases
• Three bases codon amino acid
• A number of codons strung together code for a
  gene which codes for a protein
• Functional genomics what the genes do

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Structural Genomics The Human Genome

• Three billion bases long (800 Tanachim)
• Codes for 30,000 to 80,000 genes
• 23 chromosome pairs (24 in chimp)
• 97 of genome does not code for translatable
  protein products
• June 26, 2000 Clinton and Blair announce rough
  draft

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Functional Genomics

• Sequence/structural motifs in proteins ie
  functional class of protein
• Homology to model organisms/gene knockouts
  worms, flies, mice, fish, etc.
• Antisense in cell culture
• Microarrays of gene expression
• Proteomics
• Pharmacogenomics

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Functional Genomics Motifs

• Gene families
• Super families of related activities such as
  dehydrogenases, glucocorticoid receptor-like etc.
• Bioinformatic tools data mining

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Functional Genomics Microarrays of Gene
Expression
Normal tissue
normal
Diseased
cDNA
Diseased associated
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Functional Genomics Model Organisms
Genes are just chunks of software that can Run
on any system they use the same code And do the
same jobs. Matt Ridley in Genome 1999
Perennial
Example Homeotic genes which determine macro
form of animal Fly mouse
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Functional Genomics Proteomics
Differential display of protein expression
in diseased and normal tissue
May be a better approach to target identification
than microarrays of gene expression Not all
expressed genes produce proteins
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Functional Genomics Pharmacogenomics
Genetic differences between individuals (SNP) can
cause large differences in drug effects both
agonist and antagonist and toxic Stratification
of patients into genotypes may increase the
probability of drug efficacy/therapeutic
window eg drug metabolizing enzymes,
transporters and drug receptors
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Relationship between Genes Disease

• Genes do not cause disease, defective genes cause
  disease
• One gene one enzyme (Beadle and Tatum 1940s)
• Mendelian inherited diseases
• Polygenic diseases

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Relationship between Genes Disease

• A gene is missing or defective
• Replace protein
• Replace activity
• Gene is overexpressed
• Develop inhibitors of synthesis or activity
• Poly-genic disease
• eg asthma where up to 15 genes may be involved

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Relationship between Genes Disease

• As of February 2, 2001 in GenBank
• 12265 human gene entries
• 8912 established gene locus
• 845 multi loci disease associations

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Thesis
Genomics New Drug Targets
More Rapid Drug Development
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Is Genomics Delivering? Yes but slower than
Expected. Lehman Brothers
Use of genomics to discover new drug targets
began in 1993 Today, percent of research
projects based on genomics in pharma 10-25
average Only handful of drugs currently in the
clinic utilizing genomic information Expect
percent of genomic based drugs to increase
considerably in the next 5-10 years
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The Drug Development Process
Gene Sequences Genome Targets Validated
Targets Drug Screening Drug Leads
Validated Candidate Clinical Trials
Market
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The Drug Development Process
Gene Sequences Genome Targets Validated
Targets Drug Screening Drug Leads
Validated Candidate Clinical Trials
Market
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Reality One
90
80
70
60
50
40
30
20
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0
Market
Gene Targets
Drug Candidate
Assay Development
Data from Biocentury (Jan 29, 2001) CuraGen/Bayer
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Reality Two

• Millenium 44 targets to leads
• Vertex 85 targets into phase 1
• Bayer 25 targets into phase 1

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Genomic Based Drug Development What Next?

• Improvement of bio-validation tools
• Cell based
• In-vivo based
• Better understanding of physiologic pathways and
  networks and their control
• Model organisms
• Better bio-informatic tools for protein structure
  and better chemo-informatic tools for medicinal
  chemistry