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B i o p h a r m a c e u t i c a l s L t d. 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

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Drug discovery and genomics

B i o p h a r m a c e u t i c a l s L t d.

Drug Discovery and Genomics

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


Drug discovery and genomics

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 pharma-

ceuticals.


The promise

The Promise


The concern

The Concern


Bottom line

B i o p h a r m a c e u t i c a l s L t d.

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.


Topics

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?


What is genomics

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


Drug discovery and genomics

B i o p h a r m a c e u t i c a l s L t d.


Drug discovery and genomics

B i o p h a r m a c e u t i c a l s L t d.


Drug discovery and genomics

Comparative Sequence Sizes

(Bases)

(yeast chromosome 3)

350 Thousand

Escherichia coli (bacterium) genome

4.6 Million

Largest yeast chromosome now mapped

5.8 Million

Entire yeast genome

15 Million

Smallest human chromosome (Y)

50 Million

B i o p h a r m a c e u t i c a l s L t d.

Largest human chromosome (1)

250 Million

Entire human genome

3 Billion

Return to text


Structural genomics the human genome

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


Functional genomics

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


Functional genomics motifs

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 receptor-like etc.

    • Bioinformatic tools; data mining


Functional genomics microarrays of gene expression

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 tissue

normal

Diseased

cDNA

Diseased

associated


Functional genomics model organisms

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


Functional genomics proteomics

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


Functional genomics pharmacogenomics

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


Relationship between genes disease

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


Relationship between genes disease1

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


Relationship between genes disease2

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


Drug discovery and genomics

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


Is genomics delivering yes but slower than expected lehman brothers

“Is Genomics Delivering?”“Yes but slower than Expected.”Lehman Brothers

B i o p h a r m a c e u t i c a l s L t d.

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


Drug discovery and genomics

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 Genome Targets Validated Targets

Drug Screening Drug Leads Validated Candidate

Clinical Trials Market


Drug discovery and genomics

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 Genome Targets Validated Targets

Drug Screening Drug Leads Validated Candidate

Clinical Trials Market


Drug discovery and genomics

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

Market

Gene Targets

Drug Candidate

Assay Development

Data from Biocentury (Jan 29, 2001) CuraGen/Bayer


Reality two

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


Genomic based drug development what next

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


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