Target Finding

1

• Target Finding

2
The History of Target Finding
1. The Nature Medicine Era
3
The History of Target Finding
2. The Pharmacological Era
4
Examples
gt derived from Papaver somniferum
gtderived from Salix alba
gtderived from Bufo Bufo
5
The History of Target Finding
3. The Biochemical Era
6
The History of Target Finding
4. The Genomic/Proteomic Era
7

• Biochemical Target Finding

• Many physiological and pathophysiological
  pathways in animals and humans have been solved
• Links to disease states (pathophysiology) have
  been disclosed in in-vitro and in-vivo models
• Possible drug targets are deduced from this
  knowledge

8
Example I Aspirin, the most famous drug of the
world

• Pain reliefer
• Anti-inflammatoric
• Anti-thrombotic

9
Aspirin Mechanism of Action
The Arachidonic Acid Pathway
10
Aspirin Mechanism of Action
The Arachidonic Acid Pathway
11
Aspirin Mechanism of Action
The Target Cyclooxygenase-1 (COX1)
12

• Biochemical Target Finding
• Example II Blood Coagulation/Thrombosis

13
The Blood Coagulation Cascade
14
Thrombin An Antithrombotic Target
15

• Biochemical Target Finding
• Example III Cell cycle regulation (cancer
  therapy)

16
Cell Cycle Regulation
M
(G2? M)
Growth factors

• Cell cycle is a program for cell division
  (proliferation)
• in cancer cells, there are disfunctions of this
  program
• Many different proteins are involved (e.g.
  kinases, phosphatases etc.)
• gt Important drug targets for cancer therapy

G2
CDK1
CDK4/6
Cyclin B
T
Cyclin D
T
p16
P
P
G1
Rb
Rb
P
p21, p27
E2F
T
E2F
T
CDK2
S
CDK2
Cyclin A
Cyclin E
(G1? S)
17
Cell Cycle Regulation
Cyclin-dependent kinase 2 (CDK2)
18

• Genomic/Proteomic Target Finding

19

• Genomic/Proteomic Target Finding

• About 31,000 human genes have been disclosed by
  the Human Genome Project (HUGO)
• Estimated 300,000 different proteins in humans
• Disease relevance of gt99 of these proteins is
  unknown so far!
• ? Question Which of these proteins are potential
  drug targets?