Transcript Drug Discovery and Genomics

Drug Discovery and Genomics
How the Sequencing of the Human
Genome and Related Developments
has Impacted Drug Discovery
B i o p h a r m a c e u t i c a l s L t d.
“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 pharmaceuticals.
B i o p h a r m a c e u t i c a l s L t d.
The Promise
The Concern
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.
B i o p h a r m a c e u t i c a l s L t d.
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?
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
B i o p h a r m a c e u t i c a l s L t d.
B i o p h a r m a c e u t i c a l s L t d.
Comparative Sequence Sizes
(yeast chromosome 3)
Escherichia coli (bacterium) genome
Largest yeast chromosome now mapped
Entire yeast genome
Smallest human chromosome (Y)
Largest human chromosome (1)
Entire human genome
(Bases)
350 Thousand
4.6 Million
5.8 Million
15 Million
50 Million
250 Million
3 Billion
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
Functional Genomics:
Motifs
• Gene families
– Super families of related activities such as
dehydrogenases, glucocorticoid receptorlike etc.
– Bioinformatic tools; data mining
B i o p h a r m a c e u t i c a l s L t d.
Functional Genomics: Microarrays
of Gene Expression
normal
Normal tissue
Diseased
cDNA
Diseased
associated
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.
Relationship between
Genes & Disease
• As of February 2, 2001 in GenBank
– 12265 human gene entries
– 8912 established gene locus
– 845 multi loci disease associations
B i o p h a r m a c e u t i c a l s L t d.
Thesis
Genomics
New Drug Targets
More Rapid Drug Development
B i o p h a r m a c e u t i c a l s L t d.
“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
B i o p h a r m a c e u t i c a l s L t d.
The Drug Development
Process
Gene Sequences
Drug Screening
Clinical Trials
Genome Targets
Drug Leads
Validated Targets
Validated Candidate
Market
B i o p h a r m a c e u t i c a l s L t d.
The Drug Development
Process
Gene Sequences
Drug Screening
Clinical Trials
Genome Targets
Drug Leads
Validated Targets
Validated Candidate
Market
B i o p h a r m a c e u t i c a l s L t d.
Reality One
90
80
70
60
50
40
30
20
10
0
Data from Biocentury (Jan 29, 2001) CuraGen/Bayer
B i o p h a r m a c e u t i c a l s L t d.
Reality Two
• Millenium: 44% targets to leads
• Vertex:
85% targets into phase 1
• Bayer: 25% targets into phase 1
B i o p h a r m a c e u t i c a l s L t d.
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
B i o p h a r m a c e u t i c a l s L t d.