Drug targets Flashcards
What is a drug target?
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
What is the mechanism of enzymes?
Reversible and Irreversible inhibitors
What is the mechanism of receptors?
Agonists and Antagonists.
What is the mechanism of viral surface proteins?
Block entry into cell.
What is the mechanism of ion channels?
Block or open channel
What is the mechanism of transporters?
Block or promote transport
What is the mechanism for nucleic acids?
Inhibit function, prevent gene expression
What makes a good target?
- 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
State the drug target concepts.
- 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
What is target validation?
- 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
Define a valid target.
- A target that when modulated pharmacologically, provides meaningful
efficacy and acceptable safety for specific human disease in long-term
clinical usage.
What is proof of concept?
- 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.
What is target identification?
- The generation of scientific evidence that a manipulatable able target is involved in some significant way in a disease process
Describe the process of validation.
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.
State the major components of target validation in increasing importance (human data)
- Tissue expression
- Genetics
- Clinical experience
State the components of target qualification in increasing importance (preclinical data)
- Pharmacology
- Genetically engineered models
- Translational endpoints
Describe tissue expression relationship to disease
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
Describe the genetic relationship to disease.
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
Describe clinical trial data and validation.
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
Describe preclinical pharmacological validation.
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
Describe genetically engineered models.
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
Describe translational endpoints.
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
How do you identify a valid target?
- 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
State the importance of drug target specificity and selectivity.
- 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.
