Drug repurposing Flashcards
Signature matching
• comparison of the unique characteristics or ‘signature’ of a drug against that of another drug, disease or clinical phenotype
Pathway analysis and network mapping
• describing relationships between genes or proteins in sequence (pathways e.g. extracellular ligand-receptor-intracellular signalling pathway) or network (with more complex interrelationships e.g. between genes/proteins in different pathways)
Molecular docking
• - structure-based computational strategy to predict binding site complementarity between a drug and therapeutic target
Genetic association studies
- Genome-wide association studies - hypothesis-generating method to analyse variants systematically across the entire genome (i.e. “genome-wide”) for association with a phenotype of interest
- Mendelian randomisation - uses genetic variants identified from GWAS as proxies to investigate causal effect of ‘exposure’ (e.g. variation in genes encoding proteins corresponding to drug target) on ‘outcome (e.g. disease of interest)
Retrospective clinical analysis
• Association studies in large clinical databases to look for associations that existing therapies for one indication have a beneficial effect for another indication
High throughput screening
- The use of automatic equipment to test thousands to millions of samples rapidly; in drug repurposing it tests the effect of each of a large panel of compounds and may be:
- Phenotypic screening - tests whether any of a panel of compounds cause a desirable change in phenotype in cells or animal models
- Target-based screening - tests whether any of a panel of compounds have a physical association with the target protein of interest
CASE STUDY 1 – Contergan known as thalidomide
CASE STUDY 1 – Contergan known as thalidomide - • Effective hypnotic drug
• Marketed in 1957 to treat morning sickness
• No regulatory approval required
• Caused severe skeletal birth defects
Eryhtema nodosum leprosum ENL – Immune modulated leprosy condition - • 1964
• Used thalidomide to help patient with painful ENL sleep
• Healed sores and eliminated pain
• Clinical trials – ENL patients enjoyed remission < 2 weeks
• Thalidomide later found to be a tumour necrosis factor inhibitor
Angiogenesis inhibitor • 1994
• Found that thalidomide affects blood vessels – stops them growing
• Could be used to stop tumours?
• Mechanism of adverse effect on limb development
Multiple myeloma – cancer in plasma cell • Modern day
• Thalidomide treatment for myeloma available
Thalidomide repurposed • An unsafe hypnotic
• A TNF-alpha inhibitor – anti-inflammatory indicated for ENL
• An angiogenesis inhibitor
• An immunomodulator – licensed for treatment for multiple myeloma
What is drug repurposing?
- Process of finding new uses for approved or investigational drugs outside the scope of the original medial indication
- Also referred to as repositioning, reprofiling and retasking
Why repurpose?
- Reduced risk of failure – safety evaluation in pre-clinical models, early phase human trial already done
- Shorter time for development – formulation development may already be done
- Less investment need – potential cost saving on pre-clinical and phase 1 trial
- May reveal new targets and pathways for future drug development
Repurposing strategy
- Hypothesis generation – identify candidate
- Mechanistic assessment – does drug have expected new effect
- Evaluation of efficacy – phase 2 clinical trial
Identifying drugs
Observation/ chance finding:
• Understanding of pharmacology of drug
• Retrospective analyses of clinical effect of drug
Systematic:
• Computational - systematic analysis of data to develop repurposing hypothesis
• Experimental – systematic screening of compounds for target interactions or disease-relevant effects in model systems
CASE STUDY 2 – Duloxetine
- Blocks serotonin and noradrenaline reuptake in the synaptic cleft
- Improved mood – antidepressant
Scientists realised that these neurotransmitters were important in bladder control Potential treatment for stress urinary incontinence
• Clinical trials – now licensed
CASE STUDY 3 - Sildenafil (Viagra)
- Thought it would be a good drug for cardiovascular stuff
- FOUND NO effect on coronary blood flow
Some volunteers reported strong erections
• Researcher read report identified PDE5 as key enzyme in pathway mediating erections
• Helped with erectile dysfunction
Data about drugs
• Use drug libraries
Data about diseases and drug targets
- Omics datasets
- Large retrospective clinical datasets
- Combined datasets
What is a drug library?
observations finding
- Collection of drugs
- Pharma, commercial, academic
- Unselected compounds 100,000s
- Drugs tested in clinical trials – that have or not have reached approval
Content • Physical compounds • Known activities and clinical indications • Adverse events • Structure
Omics
observations finding
Able to identify • DNA (Genome) • RNA (transcriptome) • Protein (proteome) • Metabolites (metabolome)
Genome
observations finding
• All genetic information – DNA - coding, non-coding
Describing the genome
• Genome map – major landmarks
• Genome sequence – all nucleotides
Genetic variation
• Single nucleotide polymorphism
• Short insertions/deletions
• Other structural variants
Genomics, disease and drug targets
observations finding
Genome-wide association studies GWAS
• Look for genetic variants associated with common diseases
• Biological insights
• More like to code for proteins that are druggable
Mendelian randomisation
• Use genetic variants as proxies to investigate causal effect of exposure
• E.g. variation in genes encoding proteins corresponding to drug targets
Disease phenotype
observations finding
- Variable compare differences in transcriptome/proteome/metabolome between disease and health
- Changes all the time so harder than GWAS studies
- Your metabolome can be different in morning and night
Large scale clinical data
observations finding
Electronic healthcare records
• Structured data – lab tests, drug prescribing info
• Unstructured – symptoms, signs, imaging
Pharmacovigilance datasets (WHO) • Patient, disease and drug data
Clinical trial data sets
• Patients
UK biobank
observations finding
- Large scale biomedical database
- Half a million UK participants
- In depth genetic and health info
Computational approaches
Systemic findings!
Signature matching
• Comparison of unique characteristics of drugs against another drug, disease
Molecular docking
• Structure based computational strategy to predict binding site complementarity between drug and target
Genetic association studies
• Genes associated with disease may be potential drug targets
Pathway or network mapping
• Constructing drug or disease networks based on gene expression patterns, disease pathology, protein interactions or GWAS data
Retrospective clinical analysis
• Systemic analysis of large datasets to identify drug-disease associations
Experimental approaches
Systemic findings!
- Phenotypic screening - tests whether any of a panel of compounds cause a desirable change in phenotype in cells or animal models
- Target-based screening - tests whether any of a panel of compounds have a physical association with the target protein of interest
