Drug design 7th Flashcards
What is the rationale drug design
- identify a receptor or enzyme relevant to the disease you want to design a drug for
- elucidate the structure and function of this receptor or enzyme
- design the drug molecule that interacts with the receptor or enzyme in a therapeutically beneficial way
what key questions should you ask when designing the drug
– will the drug bind to a specific molecule or more than one ?
why?? binding to other molecule might lead to adverse effects
– how well does the drug bind to the target molecule ?
why? if it cant bind to the target well, it is useless
– the shape and charge of the drug
why?? it affects the way it binds to the target, and ADME Pharmacokinetics / plasma concentration
How is the PI3K pathway deregulated
Loss or inactivation of the Tumor supressor gene PTEN
Mutstion or amplification of PI3K
Activation of tyrosine kinases growth factor receptor or oncogenes upstream of PI3K
What are the isoforms of PI3K
PI3Ka
PI3Kb
PI3Ky
PI3Kd
Properties of pI3K isoforms
PI3Ka: inhibition can lead to cancer treatment
PI3Kb: targeted for thrombosis prevention or treatment
PI3Ky and PI3Kd: targets for inflammatory autoimmune and respiratory indications
What is the active site of PI3K
ATP
What is Taselisib
Breast cancer treatment drugs that binds to the active site of PI3K
What is the definition of a objective response rate
The proportion of pts that respond either partially or fully and is a good measure of anti-tumour activity
What is the definition of pathological complete response
Absence of residual invasive cancer after the resected breast tissue and regional lymph nodes
Progressive free survival
the time from randomisation until first evidence of disease progression or death
what are the percentages of people that experienced a AE of Taselisib
32%
what are the percentages of people that experienced a AE of Taselisib
32%
Why do companies improve old drugs
Due to their adverse effects
Low specificity and selectivity
How can cancer drugs be made more specific
Add a carrier- An antibody
Benefits of antibody
Specific
Requites macrophages to clean up afterwards
what is the mechanism of the anti-body drug conjugate(ADC)
- The ACD is injected into the blood stream
- the antibodies binds to the tumour antigen
- The ADC is internalised via endocytosis
- some of the ADC are released back out of the cell
- The lysosomes fuse with late endosomes and release the active cytotoxins
- Cytotoxin interfere with critical cellular machinery
What are the problems encountered with ADC
> MAb binding-
Consider the target which is expressed on cancer cell
> Linkers
Something that is resistant to enzymes in the liver and circulatory system but is susceptible to lysosomes
> Conjugate/payload
> Fc region
Name some example of an antibody-drug conjugate
Mylotarg
Adcertis
Kadcyla
Describe the conjugation of Mylotarg
A CD33 anti-body bound with calitomyocin
Properties of Mylotarg
First ADC
Withdrawn and reintroduced with more a new indication
Causes Apoptosis
Properties of Kadcyla
EFR-ATK binding antibody
cost £90,000 Per patients
What is a biosimilar
A biological medication that is similar to current medication in the market that have the similar but not identical indication
