Drug Targets

Question 1

Empirical drug discovery is..

Answer 1

where the drug lead is effected by its useful effect e.g. penicillin.

Question 2

Rational drug discover is..

Answer 2

where the drug lead is by design or screen against biochemical target’s function.

Question 3

A drug target is..

Answer 3

a biomolecule which is present/overactive/has a function contributing to development of disease.

Question 4

What are the effects we can have on receptors? (4)

Answer 4

Ion channels - block or open

Receptors - antagonists/agonists

Enzymes - reversible and irreversible inhibitors

Nucleic acids - prevent gene expression

Question 5

Companies tend to concentrate on developing drugs for diseases with…

Answer 5

few treatment options or aim to produce compounds with better properties than existing drugs.

Question 6

What other factors need to be considered by pharmaceutical companies?

Answer 6

economic factors - they need to get financial return for their investment.

Question 7

What makes a good target? (4)

Answer 7

• must be expressed in diseased tissue.
• must be central to disease process - stops disease if hit.
• must have good knowledge of its expression, activity, role etc.
• must be druggable, must be able to develop a drug for it.

Question 8

A valid target is..

Answer 8

A target that when modulated pharmacologically provides meaningful efficacy and acceptable safety for specific human disease in long term clinical usage.

Question 9

Target validation is…

Answer 9

the process of demonstrating that engaging the target provides statistically meaningful therapeutic benefit with acceptable safety for a given indication.

Question 10

Proof of concept is..

Answer 10

preclinical or limited clinical studies prior to well powered clinical trials that establish the scientific validity and safety of a drug target.

Question 11

Validation is the process that…

Answer 11

increases our confidence in the relationship between the target and the disease.

Question 12

Major components of target validation (3)

Answer 12

• tissue expression
• genetics
• clinical experience.

Question 13

Components of target validation
Human data

Describe tissue expression: (3)

Answer 13

• target protein is expressed and active = low confidence
• if we can show the target mRNA expression is altered in the diseased tissue = medium confidence
• if we can show the target PROTEIN is altered = high confidence.

Question 14

Components of target validation
Human data

Describe genetics: (3)

Answer 14

• association between gene in small study = low confidence
• association with variant = medium confidence
• monogenic association, large effect of gene variant known = high confidence.

Question 15

Components of target validation
Human data

Describe clinical experience: (3)

Answer 15

• clinically relevant efficacy observed in a small trial but knowledge of engagement is lacking = low confidence
• clinically relevant with at least one ligand with a different mode of target or 2 ligands on biomarkers shown to predict efficacy = medium confidence.
• at least one ligand with analogous mode of action that has approval efficacy = high confidence.

Question 16

Components of target qualification: (3)

Answer 16

Pharmacology

Genetically engineered models

Translational endpoints

Question 17

Components of target qualification:

Pharmacology (3)

Answer 17

• tool (small molecule) modulates disease associated pathway in vitro or in heterologous cell lines at appropriate concentrations.
• ligand with intended mode of action modulates disease associated pathway ex vivo or in native tissue.
• ligands with intended mode of action modulate disease associated pathway in vivo and target engagement-activity relationship established.

Question 18

Components of target qualification:

Genetically engineered models (3)

Answer 18

• genetic modulation in a non-manalpian model produces disease or treatment-relevant phenotype= low confidence
• genetic modulation in a rodent/non-human primate produces disease-relevant end-phenotype = medium confidence
• human pathogenic mutation of the target in a rodent/primate mimics disease pathway and or genetic modulation of the target mitigates the same = high confidence.

Question 19

Components of target qualification:

Translational endpoints (3)

Answer 19

• target orthology known and demonstration of target pharmacology identical to human native tissue assays = low confidence.
• PK/PD relationship and Margin of Safety established using a translational biomarker of target engagement/modulation = medium confidence.
• PK/PD relationship and Margin of Safety established using a translational biomarker historically associated with clinical efficacy.

Question 20

Phenotypes are the result of…

Answer 20

complex molecular interactions in biological networks.

Question 21

What is system pharmacology?

Answer 21

where we define the biological networks used by disease and drug action.

Question 22

System pharmacology allows us to…

Answer 22

define mechanism for efficacy and define risks associated with ‘on target’ and ‘off target’ effects.