Drug Design: Basic Research, Clinical Trials Flashcards
How come death from heart disease is going down in Canada?
This death rate is shrinking, because we know the risk factors and we have developed drugs to treat these risk factors
What types of clinical trials are we most initiating?
25% for cancer
11% for the CNS diseases, (Alzheimer’s and Parkinson’s)
Not easy to come up with a new drug, very few succeed to go to clinical trials
(2016)
What types of drugs are people spending money on in Canada?
People with chronic disease, inflammatory conditions 12.7% for chronic arthritis
11.7% for diabetes
(arthritis, diabetes)
What are 3 main goals for the future?
- Personalized therapy (everyone’s different, how much a drug works and the side effects are different, want to know which drug is best for which person)
- Biological Drugs: antibodies, cytokines, cells (things that are developed by biological systems not chemical synthesis)
- New treatments for cancer (understand more the genetic alterations in different types of tumors, what are the specific mutations in each persons specific tumor)
Drug discovery, how are drugs found?
- From the Lab to the Patient
- Research at the core, on pathology, understanding what’s wrong in the specific disease
- Research in the pharmacology departments in big compagnies
- The pharmaceutical companies spend the most -1/4 on research
- Its harder and harder to find a new drug, need to check new technologies, side effects
- Cost is higher and higher
What do newer drugs focus on?
Neurology, Oncology and infectious disease
What types of drugs are being approved more now?
The types of drugs approved are changing, proteins, antibodies, nucleotides
Biological drugs: from living organisms/cells (insulin)?
Monoclonal antibodies, developed in mice, designed to target a specific component, they are increasing in use
By finding the genetic variability in the cancer we can develop antibodies for it
Inflammatory disease also uses monoclonal antibodies, arthritis
What does it take to develop a novel drug?
- 2 billion or more for each drug
- 150 researchers
- 14 years, 10 years to get the patents
- Lucky to get one out at the end of all this cost
It is hard to get a drug to market?
More and more challenging for new drugs, a lot of drugs going into clinical trials for Alzheimer’s have not succeeded
Hepatitis C drugs, many side effect, but one drug worked, and people can be treated and not get liver cancer, only need one of the hundreds to work
Why do so many drugs entering clinical trials for Alzheimer’s fail?
Alzheimer’s, we don’t know what makes it abnormal, we know what is not normal, but don’t know why
Many drugs got to clinical trials but they were pretty much unsuccessful
So many drugs in the pipeline for Alzheimer’s right now, so much work into this, need to understand more about the pathogenesis
New Drugs for Alzheimer’s?
An antibody against the amyloid plaques, supposed to stop the plaques from forming
Aducanumab treatment: reduced progression of disease
Approved in the US, not in Canada
Very expensive, small benefit if any based on the drugs already on market
None provide more than a brief, mild benefit
Inhibit acetylcholinesterase (more acetylcholine improve brain activity, doesn’t work for too long)
Inhibit NMDA receptor
Amyloid antibody
But… new drugs this year look more promising
Chronic diseases we need to cure or prevent? (3)
- Parkinson’s
- Alzheimer’s
- Arthritis
All these require basic research
Common killers we need to prevent/cure? (2)
- Cancer
- Cardiovascular – MI and stroke
All these require basic research
Global concerns? (2)
- Emerging infections (covid)
- Pollution
All these require basic research
Basic research in the government?
Basic research done in universities, funded by CIHR in Canada and the NH in the US
Some of the translational research done in universities too
Basic research and industries?
Industry does some basic research but focus more on the translational research (take basic and make something workable out of it) and clinical research
What are some ways to study the pathogenesis? (3)
Look at how cells work
Gene knockout
Develop specific antibodies
What are the current drug targets?
- Enzymes
- Receptors
- Unknown
- Physicochemical
- Monoclonal AB
- Ion Channels
- Transport proteins
- DNA/RNA, ribosome
Mainly enzymes and receptors, major targets
What is the target for AIDS?
Enzyme for AIDS is the target,
Most on the surface of the cell but some in the cell, estrogen receptor
Reasons for drug failure?
multiple control pathways interact
Human cells are complex, many interactions, need to unravel all the components which takes a lot of time and effort
Genomics and developing drugs?
Understanding the genome
What’s in it
Slowly getting to know the genetic abnormalities in specific diseases
Develop gene therapy to replace defective one in the cell
Cystic Fibrosis research?
Know the genetic abnormalities on it
Deliver a specific gene in the airways of an infected person
Make very thick mucus get an obstruction
Still being studied
Trials not successful
November 16th, 2023
Britain approves the world’s first gene therapy?
CRISPR-based treatment for sickle-cell disease and thalassemia
First successful gene therapy
Clinical trials all completed, works
Sickle cell disease, not normally shaped RBC, don’t transport O2 well, can vary in intensity
Thalassemia much worse, monthly transfusions, serious problems
Gene therapy, able to replace the malfunctioning gene with the CRISPR gene, (know exactly what gene is malfunctioning)
Patient profile?
By finding the differences between people we can find the disease mechanism
Understand the pathogenesis also
Measuring the gene expression?
- Response to stimuli: environmental changes (like drugs or disease) often cause changes in expression
- Disease markers and drug targets: changes in expression associated with disease can be diagnostic markers and/or suggest novel pharmaceutical approaches
Microarray technology?
Understand changes in DNA
Can label DNA and read it
Want to develop drugs to find a target ligand?
Develop different drugs to interact with the active site of the enzyme, need to develop many drugs to find one that binds with a high affinity and specificity
Combinatory chemistry?
Preclinical testing some compounds are good
Go back to library and find the similarities with the good ones
Find a lead compound then, make more of the lead to find the best
Combine the various parts of the molecule all at one, get a mixture of products and can test what parts work better
Make many compounds, pick a few that are very good
Robotics: High throughput screening?
Need a way to test all the compounds efficiently
Chemical synthesis, robot testing everything
Mass screening
Invitro studies – random high-volume screening and combinatorial chemistry (go through thousands of compounds)
High throughput screening looks at what, how many?
Robotics and bioinformatics: 20,000 compounds/day
Look for agonists or antagonists of the target
What are the test systems for high throughput screening?
Test system: mammalian cells, microbes, human hepatocytes, microsomes, synthetic membranes
(the things used to test the compounds in the system are varied)
Two general types of high throughput screens?
Cell-free: ligand receptor interactions
Cell-based: multiple targets (living cells, what drugs interact)
How to detect through quantification?
Fluorescence, luminescence, enzymatic, radioactive, immunological labels
What 4 basic elements does HTS require?
- Suitable compound libraries
- Assay method configured for automation (can’t test one at a time, need thousands to be tested)
- Robotics workstation
- Computerized system capable of handling the data
Conducting a reporter gene assay?
To detect target gene expression, luciferase linked to a specific gene, went it binds the gene it gives off luminescence
Subcellular fractions, in testing systems?
Look at target proteins, look for drugs that bind it, a mixture with different drugs, isolate the protein see what bound to it, run through mass spectroscopy, and get the structure of the drug
Can use living systems as test systems?
classic one is zebra fish
Can label the vasculature of the zebrafish and also label the young vasculature of the young zebrafish, angiogenesis, the formation of new blood vessels
Can label anything and see if it’s altered by a drug
Can initiate cancer in zebrafish and then test for something that will prevent the progression or improve the tumor
You would screen the zebrafish before you use the drug in rat/mouse or humans
Use juvenile, to be stuck in the wells and test what will have an impact in tumor growth
What can HTS NOT evaluate?
- Bioavailability (need to do this in a live animal)
- Pharmacokinetics
- Toxicity
- Mutagenicity (it could cause cancer)
- Specificity (what are the side effects)
Look at yeast living system?
Label the DNA repair gene with Jellyfish fluorescent protein
Expose yeast to mutagens that might cause cancer if DNA repair gene activated it will fluoresce
What is chemotaxis and metastasis?
Cancer cells spread, motile, into circulation = metastasis
Chemotaxis, cells pull other cells into the area
Can test if they will cause movement
Can create better candidates continuously?
Test and test, optimizer, test again to get a clinical trial drug
By modifying a lot might find a better more specific drug
What does the new drug Ibrutinib do?
blocks enzyme overexpressed in B cell malignancies: approved in 2014
Treats chronic lymphocytic Leukemia, can live normal life with few side effects, targets specific enzyme that is overexpresses
New drug for heart disease, block the enzyme that lowers LDL receptors?
More LDL receptors, less cholesterol build up
PCSK9: blocks cholesterol removal by the liver, so inhibit it more cholesterol broken down
Statins stop cholesterol formation also helps
What is biosimulation?
Biosimulation: computer-aided mathematical simulation of biological processes and systems
- Increasingly used to predict drug effects (positive and negatives)
What is hybridoma technology?
Method of producing large amounts of identical antibodies or monoclonal antibodies
What are different types of antibodies?
- Chimeric antibodies (mouse variable region + human constant regions)
- Primatized antibodies (chimeric with primate-derived variable regions)
- Humanized antibodies (all human except antigen recognition site)
- Transgenic mouse antibodies: fully humanized antibody
What is a monoclonal antibody?
Clones of just one antibody, bind only one antigen
Monoclonal antibody successes in 3 areas?
Autoimmune disorders
Cancer
Osteoporosis