week 8 part 2 Flashcards
Why do most compounds not become medicines?
- complex disease targets
- Too long in the body
- Adverse reactions
- Poor Absorption
- Low levels in the body
- Not effective enough
- Not sufficiently selective
- Side effects
- Unsafe
- Unstable
- Competition
- Impractical to make
What is pharmacogenomics?
The application of genomic technologies such as gene sequencing, statistical genetics, gene expression analysis to drugs in the clinical development and on the market
What does pharmacogenomics apply to?
large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways.
What is the potential implication of pharmacogenomics in clinical research/medicine?
disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients
What is the possibility of defining patient population genetically?
improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology
Where does genetics and genomic fits in?
Its Important in target validation, you can use omics and genetics to identify and validate targets
in lead candidate stage where you are testing for molecule in animal model. what should you look for?
at evolutionary fidelity of animal model
does target in animal model predict action of that target in humans or have evolutionary events caused the function of that target to divergence in animals
What happens in phase I in humans?
- use expression data
- Pathway knowledge
- Anticipate common adverse events that is related to safety
What happens in phase II in humans?
- look at efficacy of drugs
2. Look at common variants
What is pharmacovigilance?
the practice of monitoring the effects of medical drugs after they have been licensed for use, especially in order to identify and evaluate previously unreported adverse reaction
Target ID and validation?
Identification of drug targets based on biological rationale and known small molecule tractibility
Hit and Lead ID
Configure and run high throughput screen to ID bioactive small molecules
identify drug-like lead molecules
Lead to Candidate
Medicinal chemistry to optimise lead properties
Back up lead
Evaluate drug pharmacology in preclinical model
Phase I
Evaluate clinical pharmacology of candidate drug in 20-100 healthy human volunteers
Phase II
Determine therapetuic dose
Evaluate drug efficacy to achieve POC
conducted in 100-200 patients
Phase III & Market
Large comparative study (compound vs placebo) in 1000s of patients to establish clinical benefit and safety
Drug launch and subsequent safety surveillenace
What is Target Validation?
Target validation is the process by which the predicted molecular target – for example protein or nucleic acid – of a small molecule is verified
ongoing process
What does Target Validation include?
- Determining structure-activity-relationship of small molecules
- Generating a drug-resistant mutant of presumed target
- knockdown or overexpression of presumed target
- Monitoring the known signalling systems downstream of presumed target
When can you say a target is validated?
when a drug has been working in the clinic safety and effectively for many years
What is a great example of target validation?
Cox-2
What is Cox-2?
Pain target
target of cox2 inhibitors
What is a dual inhibitor?
Aspirin
Work on Cox-1 and Cox-2
What showed great efficacy in pain?
Selective Cox-2 inhibitors
What is integral to target validation?
Population safety
What is Cox-2 directly marketed in the US for pain?
Age related pain osteoarthritis
What was Cox-2 marketed as?
Tool for healthy life style
What are the 2 Cox enzymes?
Cox-1 and Cox-2
Exist in blood vessels
in an equilibrium
What happens when you inhibit COX2?
Disrupt that equilibrium and it causes clumping of platelets
make platelets much more easily coagulable
it causes an increase in vascular events
What did they found out ?
Cox2 inhibitors had 50% of cardiovascular events than people that didnt take Cox2 inhibitors
When a drug described as safe?
At the right dose
What are the perspectives on target validation and safety?
- Biology
- Variation
- Similarity
- Tractability
What is biology?
- Biological mechanism
- Disease association
- Tissue expression
- Pathways
What is variation?
- Genetic variation
- Isoform/splicing
- Epigenetics
What is similarity?
- Orthology (animal models)
2. Homology (off target effects)
What is tractability?
- Druggable
- Biopharmable
- Other e.g. siRNA
- Robust assay
What fits into the target discovery and validation?
- Talking about genetics and genomics
What are some examples of validating targets?
- Look at cell models - cancer cell models to see if a gene is differentially expressed in cancer
- Clinical samples
- RA - looking at synovium of arthritis patients to look at genes that are upregulated/downregulated - Look at animal models
What do you look for in a gene expression proteomics?
Altered expression in the disease state using genetics
What do we need to consider for a target?
Pathway context
What is a pathway in drug discovery?
A target in a linear pathway
modulate that pathway
downstream effect which is specific and predictable
What is the reason why many drugs have side effects and adverse effects or lacking efficacy?
Pathways are complex
knowledge of pathway is incomplete
What may a target acting as a single critical node control?
influence many processes
What can network interactions be?
Redundant
What can drugs interact with?
Multiple targets
What are a consequence of interaction with multiple targets?
Efficacy and safety
What are crucial considerations in drug discovery?
- Pleiotropy
2. Redundancy
Where is intervention easier in?
Simple pathways
What does crosstalk between pathways introduce?
Complications to aspect of drug actions
What may efficacy call for?
Combination of therapy or poly-pharmacology
Why are no drugs completely effective?
Complexity of biology
What is pathway: STITCH good for?
- Simple interface
- Add multiple genes
- Identify interaction
- Identify known drugs
- Expand network
What is Pathway analysis: ENRICHR good for?
♣ This tool allows u to look for enrichments of pathways in a gene set and gives u drug disease activity
ENRICHR
- Simple Interface
- Add multiple genes
- Transcription
- Pathways
- Ontology
- Diseases
- Drugs
What do we look for when doing pathway analysis?
Multi-omics
- Different genomic platform
- Gene expression genetics
- Proteomics
- Drug response data
What are the 3 Endotypes in Rheumatoid Arthritis Synvovium?
- Fibroid
- Myeloid
- Lymphoid
Fibroid
- Fibroid gene that doesn’t have much inflammatory signal
2. Plasma cells, B cells and T cells - don’t have a lot of immune cells infiltrating the tissue
Myeloid
More immune cells infiltrating the tissue but is different to fibroid subtype
Lymphoid group
Most trackable subtype
lots of plasma cells and b cells that are coming out of the blood into tissue forming ectopic lymphoid structures- lots of b-cells in the joints
What is effective in lymphoid subgroup
drugs called rituximab which targets CD20 which is b-cell receptor
What is an advantage of targeted clinical trial ?
higher response and therefore u could demonstrate efficacy of drug much more clearly and unequivocally
What is a powerful way of validating targets?
GWAS
What is one of the first successful GWAS for target validation ?
welcome trust case control consortium
study looked at 7 diseases
What are the 7 diseases that case control consortium study look at?
- Coronary artery disease
- Crohn’s disease
- Hypertension
- Rheumatoid arthritis
- Type 1 diabetes
- Type 2 diabetes
- chromosome
Where did coronary artery have a big signal in?
Chromosome 9
Where did RA and type 1 diabetes have a big signal in?
Chromosome 6
What is the HLA region?
♣ Both ra and type 1 diabetes have a signal in the same region of the genome
What is interesting about Chrons disease (IBS)?
- Loads of associations
What is autophagy?
a process by which the cells clean up debris in the body
What does Crohn’s disease have?
Defective autophagy phasethe gut is not cleaned up properly which causes iBS and inflammation
What has GWAS given us?
thousands of genetics susceptibility loci
What was observed in GWAS catalogue?
- 800 publications of gene disease associations
2. identified 991 disease genes based on genetics
Therapeutic opportunities from GWAS
15% of these genes would be druggable and 25% of genes are biopharmable
What does the database pharma projects have?
information about which targets that they worked on by companies
What was the associations with statins?
- HMGCR
- hypercholesterolemia
- LDL cholesterol
What is statin target?
- ♣ HMGCR
2. associated with cholesterol level in genetics
What is SLC30A9?
transport associated with type2 diabetes
What association was found with hypertension?
NR3C2
Na+ channel- this is associated with blood pressure
What is fludrocortisone ?
known agonist of this target and its indicating for cerebral salt wasting syndrome and a side effect of that drug is that it causes hypertension
What is variation in drug response mediated by?
- Pharmacodynamics
2. Pharmacokinetics
Pharmacodynamics
Relationship between drug concentration and effect
“what the drug does to the body”
Pharmacokinetics
Study of drug Absorption, Distribution, Metabolism and Excretion
“what the body does to the drug”
What are critical determinants of efficacy and safety?
PK/PD properties
What are PK/PD properties mediated by?
10s-100s genes
What is pharmacogenetics?
study of genetic variation in these genes
What does different variant of the target cause?
Different drug activity
When does a target not bind to drug very well?
might get variants that mutate target binding site
What is Beta2 adrenergic receptor ?
target of formoterol in asthma – inhaled drug
most common most widely used drugs
they have high rates of incomplete efficacy
What are 2 areas of pharmacogenetics?
- Efficacy
- Adverse events
looking at responders and non-responders
Ideally, what are drugs?
- Given orally
2. Gut absorbed
What is the liver?
Principal organ of drug metabolism, although every biological tissue has some ability to metabolise drugs
Where does drug pass through?
Liver into circulation
The percentage dose reaching the circulation is known as bioavailability
What is rate of metabolism?
Important determinant of duration and intensity of drug action
What is one of the biggest dietary effect on drug action?
Grapefruit juice
What is grapefruit juice?
potent inhibitor of cyp3a4 and other cyp aswell and these enzymes metabolize most drugs
Grapefruit kuice
Inhibitor of the intestinal cytochrome P-450 CYP3A4 which is responsible for the first-pass metabolism of many medications
Inhibition of CYP3A4 elevates serum drug concentration
e. g.
1. Lovastatin (cholesterol reducing)
2. Cyclosporine (Antibiotic)
3. Some antihistamine medications
What is a genetic cause of variation of drug action on metabolism?
CYPD26 polymorphism
Deletion of CYPD26
Poor metabolizer
What are most drugs?
will be poorly metabolized so youll be exposed to most drugs at higher dose
rapid metabolizer/ ultra rapid metabolizer
multiple copies of cyp2d6 and that means most drugs u take will be metabolized at a blink of an eye – don’t get good effect of doses – youll need higher doses
What is Avandia?
effective type 2 diabetic drug very similar to cox2 it was widely prescribed in us
Why PPARG agonist cause cardiac events?
- Type II diabetes target
- Nuclear hormone receptor
- Highly expressed in adipocytes
- Rosiglitaozne (Avandia) was a blockbuster for GSK
What are the target expression?
- GTEX
- EBI gene expression atlas
- NCBI GEO
What are the characteristics animal models should have?
Should closely reproduce the disease or condition under study
Should be an industry/academic accepted model
The data should be robust enough to be duplicated by a 3rd party
Should show statistical significance – feasible to use sufficiently large number of animals to demonstrate statistical significance
What was Monoclonal CD28 agonistic antibody (T-cell co-activator) developed as?
Drug for leukemia and rheumatoid arthritis
What should be considered when selecting animal species?
Selection pressure
What does preclinical studies in animal aim to accurately predict?
Drug action and safety in man
When are preclinical studies only valid?
when the function of the gene is equivalent (orthologous) between the model and man
What are 3 types of selection pressure?
- Negative selection
- Neutral selection
- Positive selection
Negative selection
Deleterious mutations are selected against to conserve function
Neutral selection
Neutral mutations are unaffected by selection
Positive selection
Advantageous mutations are selected for. Positive selection is indicative of functional change
DGIdb
put a list of genes and it will tell you whether they are druggable or whether theres a drug that’s already been used for that gene
Lipinski’s rule of 5
- No more than 5 hydrogen bond donors
- No more than 10 hydrogen bond acceptors
- A molecular mass less than 500 daltons
- An octanol-water partition coefficient [5] log P not greater than 5
Lead like rule of 3 (RO3)
MASS <300D H donors , < =3 H acceptors, < = 3 rotatable bonds
What is connectivity map?
Database developed in rodents in Boston
They took 4 cancer cell lines
And each of these cell lines in-vitro they exposed to separately to 3000 FDA approved drugs
