Drug targets

Question 1

What is a drug target?

Answer 1

A bio-molecule which either:
– Is present in the diseased tissue
– Has elevated expression in the diseased tissue
– Is overactive in diseased tissue
– Has a function contributing to development or existence of
disease
– Has an involvement or role in disease process

Question 2

What is the mechanism of enzymes?

Answer 2

Reversible and Irreversible inhibitors

Question 3

What is the mechanism of receptors?

Answer 3

Agonists and Antagonists.

Question 4

What is the mechanism of viral surface proteins?

Answer 4

Block entry into cell.

Question 5

What is the mechanism of ion channels?

Answer 5

Block or open channel

Question 6

What is the mechanism of transporters?

Answer 6

Block or promote transport

Question 7

What is the mechanism for nucleic acids?

Answer 7

Inhibit function, prevent gene expression

Question 8

What makes a good target?

Answer 8

• Must be differentially expressed / regulated/ located in diseased tissue
• Must be central to disease process with robust studies in clinical samples
• Must be characterised in terms of expression, activity, function and role

Question 9

State the drug target concepts.

Answer 9

• Clinical data define clinical relevance
• Make drugs for disease, don’t find diseases for drugs
• A good drug for a bad target won’t change disease
• A bad drug for a good target often works
• Chemical starting point shouldn’t define biology strategy
• Results of a screen don’t affect relationship between target and disease
• Ease ≠ Disease

Question 10

What is target validation?

Answer 10

• Identifies and assesses whether a molecular target merits the
  development of drugs
• The process of demonstrating that a molecular target is a therapeutically
  relevant pharmacological target
• Target shown to be critical to disease process

Question 11

Define a valid target.

Answer 11

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

Question 12

What is proof of concept?

Answer 12

• Preclinical or limited clinical studies prior to well-powered clinical trials, that
  establish the scientific validity and safety of a drug target; it is part of the
  continuum of target validation.

Question 13

What is target identification?

Answer 13

• The generation of scientific evidence that a manipulatable able target is involved in some significant way in a disease process

Question 14

Describe the process of validation.

Answer 14

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

Demonstrates target is critical or central to disease development or
progression.

Allows exploration of effects caused by modulation of target, to identify
mechanism based adverse effects.

Question 15

State the major components of target validation in increasing importance (human data)

Answer 15

• Tissue expression
• Genetics
• Clinical experience

Question 16

State the components of target qualification in increasing importance (preclinical data)

Answer 16

• Pharmacology
• Genetically engineered models
• Translational endpoints

Question 17

Describe tissue expression relationship to disease

Answer 17

Low - Target protein is expressed or active in the desired organ/sub-region/cells

Med - Target mRNA expression is altered in the desired disease tissue/iPSCs

High - Target protein expression is altered in desired disease tissue/iPSCs

Question 18

Describe the genetic relationship to disease.

Answer 18

Low - Genetic association in small underpowered (or non-replicated studies) without functionation of the variant

Med - Replicated polygenic association with modest effect size and functioned variant OR association with common, low risk variant in a gene that also has rare variant associated with large effect size

High - Monogenic association, large effect size and functionation of gene variant known

Question 19

Describe clinical trial data and validation.

Answer 19

Low - Clinically relevant efficacy observed in a small trial but knowledge of engagement of specific target/pathway is lacking

Med - Clinical relevant efficacy observed with at least one ligand with a different mode of target modulation or with two ligands or biomarkers previous shown to predict efficacy

High - At least one ligand with analogous mode of action on the target/target pathway has ‘approvable’ efficacy in the indication of interest with robust evidence of target engagement

Question 20

Describe preclinical pharmacological validation.

Answer 20

Low - pharmacological tools e.g. small molecule, antibody, peptide/protein modulates disease associated pathway in vitro or in heterologous cell lines at appropriate concentrations

Med - Ligand with intended mode of action modulates disease associated pathway ex vivo or in native tissue

High - Ligands with intended mode of action modulate disease associated pathway in vivo and target engagement-activity relationship established

Question 21

Describe genetically engineered models.

Answer 21

Low - Genetic modulation in non-mammalian model organism produces disease or treatment-relevant phenotype

Med - Genetic modulation in a rodent/non-human primate produces disease-relevant endophenotype

High - human pathogenic mutation of the target in a rodent/primate mimics disease pathway&/or genetic modulation of the target mitigates the same

Question 22

Describe translational endpoints.

Answer 22

Low - Target orhotology known and demonstration of target pharmacology identical to human native tissue assays

Med - PK/PD relationship and margin of safety established using a translational biomarker of target engagement/modulation

High - PK/PD relationship and Margin of Safety established using a translational biomarker historically associated with clinical efficacy

Question 23

How do you identify a valid target?

Answer 23

• Genetics
  – SNPs, polymorphisms
• Clinical data
  – Disease database
• Expression patterns
  – Location, Disease modulation,
  Microarray studies
• In vitro models
  – siRNA
• In vivo models
  – Transgenic, Null / Knock-out
  mice, Behavioural models
• Model organisms
  – Drosophila, Zebrafish, C. elegans
• ‘Omics’
  – Genomics, Proteomics,
  Transcriptomics

Question 24

State the importance of drug target specificity and selectivity.

Answer 24

• Greater drug selectivity for its target produces less undesirable side effects.
• e.g., Penicillin targets bacterial cell wall biosynthesis.
• Inhibitors should only hit target enzyme and ideally show isoenzyme selectivity.
• Receptor agonist/ antagonist should interact with specific type of receptor (e.g.
  adrenergic receptor) rather than a receptor range, or even a particular receptor type
  (e.g. β-adrenoceptor) or even a particular receptor subtype (e.g. β2 -adrenoceptor).
• Targeting drugs against specific receptor subtypes often allows drugs to be targeted
  against specific organ or disease.

Question 25

Do drugs only act on one target?

Answer 25

• Drugs can and typically do act at several target sites.
• Promiscous drugs that have multiple targets

Question 26

What are orphan drugs?

Answer 26

Orphan drugs: drugs with unknown mechanism of action are frequently
found in several therapeutic categories. e.g.anti-bacterials