Drug Discovery In The Past & Personalised Medicine Flashcards
What medical treatments were previously discovered in nature (based on observation)? (4)
- Willow bark tea
- Fox glove tea
- Cow pox inoculations
- Chinese traditional medicine
What was willow bark tea used as a medicine for?
Pain & rheumatism
What was fox glove tea used as a medicine for?
Heart failure
What were cow pox inoculations used as a medicine for?
Small pox
What was morphine extracted from and what was it used for?
Extracted from the opium poppy
Used as a painkiller
What was digoxin extracted from and what is it used in?
Extracted from foxglove
Useful in the treatment of heart conditions (heart failure)
What is the limitation of traditional remedies, and how have improvements been made?
Mixtures of impure active compounds at variable and unknown concentrations
Improvements made by extracting active compounds from traditional remedies, purifying it, and giving it in a controlled concentration
What are 2 examples of drugs from natural compounds?
Morphine
Digoxin
What drug is an examples of chance identification? And who discovered it?
Penicillin
Discovered by Sir Alexander Fleming - he noticed that in one culture contaminated by mould, colonies closer to the mould had stopped growing, but those further away were growing properly
What is the difference between arsanilic acid and (discovered) Salvarsan (606) in the treatment of syphylis ?
Arsanilic acid - kills syphylis-causing bacteria but is very toxic for humans
Salvarsan (606) - kills syphylis-causing bacteria but at a much lower concentration - therefore less toxic to humans - therapeutic window is wide
What is the idea of precision medicine?
Idea that if we could stratify patients based on predicted response to the drug, we could choose drugs that are most effective
Studies have shown that variation in drug response is mainly determined by…
Genes (~inherited characteristics)
What is ‘pharmacogenetics’?
The study of variation in drug responses due to genetic variation
What are 2 genetic polymorphisms leading to variation in drug response?
- Pharmacokinetic differences in drug-metabolising enzymes and drug transporters - leads to variation in the concentration of the drug at the target
- Pharmacodynamic differences in drug target or downstream signalling effectors
How could patient genotyping improve dose selection?
To understand the pharmacokinetic differences - variation in genes that encode drug-metabolising enzymes & drug transporters which leads to variation in the concentration of the drug at the target
Determining the genotype of the patient would allow us to calculate the dose of the drug
How could patient genotyping improve drug selection?
Pharmacodynamic differences - genetic variation in genes encoding particular drug targets / proteins or downstream signalling effectors
Patient genotyping could better inform the decision on which drug to use
What is Suxamethonium and how does it work?
DNC neuromuscular blocker
Skeletal muscle relaxant
Binds to ACh receptor on neuromuscular junctions and causes prolonged depolarisation
What is the impact of patients having butyrylcholinesterase (BChE) polymorphism?
Suxamethonium is normally inactivated by BCHE enzyme in approx 10 mins
However, some patients have mutation in this enzyme, and in homozygous variation, this mutation causes dramatic reduction in enzyme activity - takes up to 10 hours
- Scoline apnoea?
To avoid this effect, patients are genotyped before Suxamethonium is given
What are statins used for?
Given to many patients to decrease the risk of cardiovascular disease
Some genetic variants in transporter gene increase the risk of…
Statin-induced myopathy
What is statin-induced myopathy?
Statin-induced myopathy is a potential side effect of statin medications, which are commonly prescribed to lower cholesterol levels and reduce the risk of heart disease.
Myopathy refers to muscle damage or weakness/
What are SNPs?
Single nucleotide polymorphisms
(Smallest unit of genetic variation)
What was discovered in the study of statin-induced myopathy and transporter polymorphism?
SNP in OATP transporter gene was found to be very highly associated with myopathy
The OATP transporter was shown to be involved in the uptake of statins into the liver for metabolism
So having this particular SNP greatly increased the risk of developing myopathy upon treatment with statins
Therefore treatment with statins could be made more safe if patient genotype was determined first
What was the process of the study of statin-induced myopathy and transporter polymorphism?
Clinical trial
6000 patients given statins - 85 developed myopathy, 90 controls selected (who had not developed myopathy)
6000 patients given placebo
Genome wide association study
>300,000 SNPs determined for each of the 85 test subjects and 90 controlled
Association with myopathy was calculated (y axis on graph)
What is an example of genetic polymorphism in the target gene?
HER2 in breast cancer
What is over-expressed in ~ 20% of breast cancer patients?
HER2 receptor tyrosine kinase
What does over-expression of HER2 in breast cancer cause?
Anti-apoptosis
Cell proliferation
What is Trastuzumab?
A monoclonal antibody against HER2
Effective drug in treatment of breast cancer patients with an over-expression of HER2
What does the (monoclonal antibody) Trastuzumab do in the treatment of breast cancer
Monoclonal antibody (Trastuzumab) binds to HER2 (RTK) - triggers immune response & prevents dimerisation (activation) of HER2 (RTK) which prevents proliferation and causes apoptosis
What technique can be used to select patients for Trastuzumab treatment?
Molecular typing of tumour
Small fragment of tissue removed from the body and analysed - HER2 comes up as brown, blue is cell nuclei - can see the level of expression of HER2
With a higher expression of HER2, the patient will benefit more than others from monoclonal antibody treatment (Trastuzumab)
HER2 RTK over-expression is found in which cancer patients?
In ~20% breast cancer patients
In ~20% stomach cancer patients
In a small proportion of oesophagus cancer patients
How can ‘liquid biopsies’ be used in the choice of precision medicines?
Liquid biopsies - small blood sample can be analysed for identifying cell fragments & nucleic acids shed into circulation by dying cancer cells
This can be used to identify components which characterise the cancer to better choose precision medicines
What two things can be used in the development of precision medicines for cancer?
Molecular characterisation (rather than anatomy / histology)
Molecular typing of tumour to identify the most effective treatment
What is cystic fibrosis and what is it caused by?
Cystic fibrosis is a common genetic disease
It is caused by mutations in the CFTR gene, which encodes the Cl- channel in apical membrane in airway and other epithelia (e.g. in intestine)
What are the 2 most common Cystic fibrosis-causing mutations?
△F508: >90% patients
G551D: <5% patients
What is the effect the G551D mutation (polymorphism) in cystic fibrosis?
G551D mutation causes defective gating in the CFTR protein which regulates the movement of chloride ions (Cl-) across cell membranes
G551D mutation means that CFTR mostly stays in the closed gate conformation. This leads to a build-up of Cl- ions in cells & tissues, which can lead to the formation of thick, sticky mucus that clogs the airways and causes respiratory problems (hallmark of CF)
What is the effect of the △F508 mutation of CFTR in cystic fibrosis?
Defective folding
- folding is inefficient so over 99% of the translated protein is degraded - reducing the amount of functional CFTR protein at the cell membrane - contributing to symptoms of CF
What is the precision medicine treatment strategy for cystic fibrosis patients carrying the G551D mutation of CFTR?
CFTR modulator
potentiator - keeps the gate of the CFTR open
Example - VX-770 (kalydeco) - causes increased lung function & dramatic improvement of health
However, this drug is ineffective in △F508-carrying patients
What is the precision medicine strategy for cystic fibrosis patients carrying the △F508 mutation that gives a moderate effect?
Combining treatments:
VX-770 + VX-809 (Orkambi)
But only gave a small improvement in lung function, reduced degradation of protein
What is the effective precision medicine strategy for cystic fibrosis patients carrying the △F508 mutation?
Trikafta:
VX-770 + VX-661 + VX-445
Causes major improvement of lung function: is a combination of 2 correctors (act on the folding) and a potentiator (keeps the gate open)
What are pharmacogenomics?
How variation in the whole genome affects the response to drugs
What is the idea of ‘theradiagnostics’?
Therapy + diagnosis
The idea is to combine these 2 elements so that the treatment is more tailored to the individual
What is an example of ‘theradiagnostics’?
Targeted radionucleotide therapy for acute leukaemia
How does targeted nucleotide therapy for acute leukaemia work?
Targets moiety (specific fragment of a molecule) by using:
Anti-CD66 monoclonal antibody (that recognises tumour cells) coupled to a diagnostic and a therapeutic radionucleotide
What is the role of the diagnostic radionucleotide (111ln) in targeted radionucleotide therapy for acute leukaemia?
- suitable for non-invasive imaging
- can be used to identify whether patients benefit from the therapy, as using the same target allows us to see where the radioactive nucleotide would be delivered
- can be used to calculate the ideal dose of radiotherapy
- can be used to assess the efficacy of the radiotherapy post-session
What is the role of the therapeutic radionucleotide (90Y) in targeted radionucleotide therapy for acute leukaemia?
- suitable for irradiation of cancer cells (to kill the cancer cells)
How does (personalised treatment) CAR-T work to treat blood cancers?
- Apheresis - patient’s T-cells (immune cells) isolated and collected from the body
- T-cells genetically modified to express chimeric antigen receptors (CAR) which can recognise and specifically kill cancer cells - become CAR-T cells
- Cells multiplied
- Cells infused back into blood circulation through IV
- CAR-T cells kill cancer cells
- Release of cytokines - to promote future killing of cancer cells
What are advantages and disadvantages of CAR-T treatment of blood cancers?
+ has been successful in some treatment of leukaemias
- however, can also have some very serious side effects (e.g. attacking non-cancerous cells)
- has lead to the development of resistant cancers (in some cases)
What is the purpose of Structure Activity Relationship (SAR) studies?
To compare and find the compound with the best characteristics
What did Sir James Black hypothesise and why?
Was studying angina - oxygen delivery to the heart is insufficient
Was studying adrenaline & noradrenaline, knew that adrenaline inc O2 requirement for the heart
Therefore hypothesised that if he could block adrenaline receptors, the situation could be improved
What was the first B-blocker to be used?
Propranolol (beta-antagonist)
What does Isoprenaline act as?
Full agonist of beta-adrenoreceptors in the heart
What does Dichloproisoprenaline act as?
Partial agonist of the beta-adrenoceptors in the heart
What does Propanolol act as?
Antagonist of beta-adrenoceptors
What did Sir James Black do in his Structure Activity Relationship study of isoprenaline and dichloroisoprenaline
After synthetic modification, produced propanolol - antagonist of beta-adrenoceptors
What is propanolol used to treat?
Hypertension, angina and other cardiovascular conditions
What did Paul Erlich & Alfred Bertheim do in their structure activity relationship study (SAR) ?
Synthesised over 600 derivatives of arsanilic acid
Found Salvarsan (606)
What are the 2 main steps in modern drug development?
- Target and lead compound (compound that acts on the target and has a desired effect) identification
- Lead compound optimisation
How is the drug target identified in drug development?
Usually proteins - surface receptors, enzymes, structural proteins
Mostly identified due to our understanding of basic mechanisms underlying disease
How is the lead compound (compound that acts on the target and has a desired effect) identified in drug development?
Biological intelligence
High-throughput screening
What are the 3 ways of lead compound optimisation?
- Increase potency
- Improve pharmacokinetics - how the drug is handled in the body; how it is distributed, metabolised & eliminated
- Minimised unwanted effects (toxicity)
What is the importance of lead identification in rational drug design?
If the structure of the target protein is known, chemical can be designed & optimised in silico
What is the drug target for thrombocytopaenia (low platelet count in blood)
Thrombopoietin (TPO) receptor
