Lec. 21 - Drug Design 1 (Basic Research) Flashcards
In recent years, what has happened to the cost of developing drugs? And the output? Why?
Cost has gone up tremendously, while output has remained fairly similar.
This is because most of the “easy” drugs have already been found and developed
What’s a newly arising type of drug? What mainly makes up this group?
Biological drugs (mostly monoclonal antibodies)
What are the phases of drug development?
Drug discovery -> pre-clinical -> clinical trials -> FDA review -> Clinic
By how much are drug candidates whittled down during drug development at each phase
Drug discovery: 10 000 compounds
Pre-clinical: 250 compounds
Clinical trials: 5 compounds
FDA approval: 1 approved drug
What is current annual cost of drug development
> 90 billion dollars
In what way is Alzheimer’s an outlier to most disease trends?
It has been stubbornly difficult to find any treatment or cure for Alzheimer’s. We still have yet to find any truly effective drugs, as we don’t even really understand the pathophysiology
What is a new drug on the horizon for Alzheimer’s in 2021? What are some downsides?
Aducanumab ->
Monoclonal antibody injection that would clear amyloid fibers from the immune system before plaques are made, which would prevent neuroglia & neuron death.
Evidence is minimal, cost is enormous and daily injections take a toll on the quality of life.
Currently rejected in Canada, approved by the FDA
What are the 2 main reasons drugs get rejected during clinical testing?
Pharmacokinetics and lack of efficacy
What is happening to the number of antibiotics going to market?
Why is this the case?
Is there some new pressure that may change this?
Fewer and fewer introduced.
Not profitable for the pharmaceutical companies, as the drugs are only sold for a few weeks and not much money can be made.
Clinical trials:
How long do they take?
How much do they cost?
What’s the success rate?
10-15 years
Up to 4 billion
Only 10% of drugs make it to market
What are the top 3 most profitable conditions for pharmaceuticals to treat?
- Inflammatory conditions
- Diabetes
- Cancer
Name 3 chronic diseases that need research (due to expanding life spans)
- Alzheimer’s
- Parkinson’s
- Arthritis
What are the 2 types of arthritis
- osteoarthritis (wear and tear)
- rheumatoid arthritis (autoimmune disorder)
What are the 2 biggest killers today?
Cancer and cardiovascular disease
Goverment vs big pharma:
Who pays most for respective phases of drug development?
Gov -> pre-clinical work (often in funding university research)
PhRMA -> mostly clinical trials
What is generally the first step in drug development?
Understanding the pathogenesis of the disorder -> if you know the problem you can try and find a solution
Name 3 examples of drug targets
What are the most common targets?
- Ligand-gated ion channel
- GPCRs
- Enzyme
Generally, receptors and enzymes
What is gene therapy?
What’s an example of a success story using this approach?
A viral vector carrying a gene is added to a cell, the gene is then inserted into the nucleus. The gene encodes for a protein that was missing in a particular disease.
Cystic fibrosis (patients for whom their lungs lack a chloride channel) can be treated this way.
How does pre-genomics (3) differ from genomics (5) when studying the pathogenesis of a disease?
Pregenomics:
- Uniform disease description
- Patient homogeneity
- Universal therapeutic/treatment strategy
Genomics:
- Disease mechanism
- Disease heterogeneity
- Individual variation
- Patient risk assessment
- Targeted care
Why do we measure gene expression when studying the disease?
-Disease markers and drug targets:
Variation could suggest novel drug targets
-Response stimuli:
Environmental factors can often cause changes in expression
Describe microarray technology
DNA complementary to genes of interest laid out on solid surface
DNA from samples eluted over surface
Complementary DNA binds
Bound DNA detected by fluorescence
What’s the (simplified) path to drugs from genomics?
Genomics -> proteomics -> structural biology -> drugs
Describe the process of finding possible ligand candidates for your target.
Using compound libraries, we can screen thousands of compounds to find ‘lead compounds’.
These lead compounds are then tested in pre-clinical trials.
If one lead compound is found to work best, you make thousands of variations to said-compound and restart the process from the top (lead optimization).
How can combinatorial chemistry be used to help find possible ligand candidates for your target?
Allows to put different part of a molecule together to test out a bunch of possibilities
How does high throughput screening help in testing possible compounds as ligand candidates for target?
Robotics + bioinformatics allow for 20 000 compounds screened per day (much quicker than manual screening).
Name the 4 requirements for High Throughput Screening
- Suitable compound library
- Assay method configured for automation
- Robotics Workstation
- Computerized system capable of handling the data
How does an automated ligand identification system work?
Combined ligands with target in vitro
Wash solution so only bound ligand remain
Mass spectroscopy to identify which ligand bound
Name 5 things high throughput screening CAN’T identify
How could this be modeled, then?
- Bioavailability
- Pharmacokinetics
- Toxicity
- Mutagenicity
- Specificity
Animal models can be used to identify these elements
How does bioinformatics play a role in drug development?
Algorithmic generation of understanding from data is how we can piece together information from the data of screening tests
How can computational chemistry be utilized in the process of drug development?
What is a prominent success story using this?
We can use software and calculations to make predictions/models about how potential drug could act on target
HIV protease inhibitor was in part developed using one of first computer-aided drug designs
What is Ibrutinib? How does it function?
A new breakthrough drug in cancer treatment.
It blocks an enzyme overexpressed in malignant B cells
How do statins help combat heart disease?
They decrease the production and release of cholesterol from the liver
What is PCK9? How does the monoclonal antibody PCK9 inhibitor function?
PCK9 degrades LDL cholesterol receptors on the liver (has effect of increasing cholesterol in circulation)
The Mab PCK9 inhibitor binds to PCK9 and prevents it from acting, thereby allowing more LDL cholesterol to clear.
What species can monoclonal antibodies be made of?
- Combinations of mouse & human
- Variable regions derived from primates
- Purely human antibodies
First 2 are called hybridomas
What are 4 strategies to avoid anti-mouse antibodies from being made in patients receiving hybridoma Mab?
Chimeric antibodies:
Mouse variable region + human constant region
Primatized antibodies:
Chimeric antibodies + primate-derived variable region
Humanized antibodies:
All human except antigen-recognition site
Transgenic mouse antibodies:
Full humanized antibody
Give examples of 4 types of disease Mab is being used to treat.
- Rheumatoid arthritis
- Chron’s disease
- Cancers
- Osteoporosis
How can Mab be used to treat osteoporosis?
Mab antibodies against osteoclasts (break down bone) to allow osteoblasts more time to build it up
Name 4 examples of cancers Mab is being used to treat
- B-cell malignancies
- Breast cancers
- Human epidermal growth factor 2 (HER2)
- Colorectal cancer
How is Mab used to fight colorectal cancer?
Tumor is analyzed to see if patient is eligible for:
-antibodies against epidermal growth factor (VEG-F)
Mab can then be used to target
- Tumor itself
- Microenvironment (surrounding tumor)
- Blood supply to tumor (angiogenesis)
What is TNF?
What is its therapeutic significance
Tumor Necrosis Factor:
Big target for Mab treatment of auto-immune diseases
Name 2 drugs that target Tumor Necrosis Factor
What do they treat?
Describe their methods of action.
Adalimumab: autoimmune diseases (rheumatoid arthritis, psoriasis, etc.)
Infliximab:
rheumatoid arthritis
Binds to TNF-alpha and reduces inflammation
What animal model is most common? What percentage of preclinical evaluations are conducted on this model
Rodents (mice and rats) comprise 90%
In what scenarios are primates mainly used as animal models?
Studies involving the brain
Gives examples of toxicity tests conducted in preclinical evaluations
-Ames test:
Tests mutagenecity
-Teratogen test:
Evaluate fetal effects in mice
-Jellyfish gene in yeast to evaluate DNA repair
Summarize the first phase of drug discovery in 5 steps
Find a target
Find a lead
Optimize lead
ADMET (absorption, distribution, metabolism, excretion, toxicity)
