Discovery Flashcards
(27 cards)
what is a drug?
A product that alleviates, cures, or prevents disease, or is intended to affect the structure
or function of the body
how long from initial “hit” do you think it takes a drug to get to market?
14 years
what are the 3 ‘D’s?
Discovery Development Delivery
Why do drugs fail?
- lack of biological activity
- cannot be used in humans
- not enough interest in compound
- lack of investment
Target based
Targets a specific protein/pathway which is essential for disease
Targets are identified
- Use recombinant proteins
or cells over-expressing the
target
- Screens used to measure
the compound’s effect on
the target
- Answers question:
“How does it work?”
Target-free (phenotypic) screening
Any screening which is not target based. Screens candidate drugs based on their desired effects
without knowing the mechanism of action
Targets are unknown
- Ideally use native human
cells
- Activity in phenotypic
screening might be
translated to human disease
more effectively
- Answers question:
“Does it work?”
pros of Target based
Target is known
- Mechanism of action is known
- High throughput screening
- Measure compound
characteristics
cons of target based
- Unsure if will translate from in
vitro to in vivo assays - Can’t measure compound
properties (toxicity, off-target
effects)
pros of Target-free
Based on desired phenotype
- Uses native human cell lines
- Simultaneously measure
compound properties
- More physiologically relevant
cons of target-free
- Target is unknown
- Low throughput screening
- Need identify the mechanism
of action
Target based assays
- Protein-protein interactions
- Enzyme activity
Target-free assays
- Cell proliferation (growth/death)
- Reporter genes (expression)
Target based & target-free strategies are not
mutually exclusive! Can be used in combination
High throughput screening (HTS)
To accelerate drug discovery by screening large compound libraries against specific targets, at a rate of over a few thousand compounds per day
Key considerations in assay development
1) Relevance
2) Reproducibility
3) Robustness
4) Feasibility
5) Automation
Hit
A compound which has the desired activity in a compound screen, & whose activity is confirmed upon retesting
Confirmatory testing
Compounds are retested using the same assay conditions to
make sure that the activity is reproducible
Lead Optimization
Following confirmation of a hit, aims to improve the lead compound by chemical modification of the lead structure to create new analogs with better effects
Secondary screen
Confirmed hits are tested
in a functional cellular assay to determine
efficacy
Pre-clinical Safety Studies
Focus on safety, tolerability, and efficacy of the drug. Can be performed in cell culture and/or animal models to ensure patient
safety
Clinical trials
Studies to find out whether the drug is safe & effective for people
Phase I clinical trials
Test an experimental drug on a small group of healthy people (20-100) for the first time
Phase II clinical trials
The drug is given to a larger group of people (usually
100+) with the disease to
Phase III clinical trials
The drug is given to even larger groups of people (1,000+) with the disease to
Phase IV clinical trials
These trials are done after the drug is approved and is on the market. They gather information
on things like the best way to use a drug, and the long-term benefits and risks
