Drug design 7th

Question 1

What is the rationale drug design

Answer 1

1. identify a receptor or enzyme relevant to the disease you want to design a drug for
2. elucidate the structure and function of this receptor or enzyme
3. design the drug molecule that interacts with the receptor or enzyme in a therapeutically beneficial way

Question 2

what key questions should you ask when designing the drug

Answer 2

– 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

Question 3

How is the PI3K pathway deregulated

Answer 3

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

Question 4

What are the isoforms of PI3K

Answer 4

PI3Ka
PI3Kb
PI3Ky
PI3Kd

Question 5

Properties of pI3K isoforms

Answer 5

PI3Ka: inhibition can lead to cancer treatment
PI3Kb: targeted for thrombosis prevention or treatment
PI3Ky and PI3Kd: targets for inflammatory autoimmune and respiratory indications

Question 6

What is the active site of PI3K

Answer 6

ATP

Question 7

What is Taselisib

Answer 7

Breast cancer treatment drugs that binds to the active site of PI3K

Question 8

What is the definition of a objective response rate

Answer 8

The proportion of pts that respond either partially or fully and is a good measure of anti-tumour activity

Question 9

What is the definition of pathological complete response

Answer 9

Absence of residual invasive cancer after the resected breast tissue and regional lymph nodes

Question 10

Progressive free survival

Answer 10

the time from randomisation until first evidence of disease progression or death

Question 11

what are the percentages of people that experienced a AE of Taselisib

Answer 11

32%

Question 11

what are the percentages of people that experienced a AE of Taselisib

Answer 11

32%

Question 12

Why do companies improve old drugs

Answer 12

Due to their adverse effects

Low specificity and selectivity

Question 13

How can cancer drugs be made more specific

Answer 13

Add a carrier- An antibody

Question 14

Benefits of antibody

Answer 14

Specific
Requites macrophages to clean up afterwards

Question 15

what is the mechanism of the anti-body drug conjugate(ADC)

Answer 15

1. The ACD is injected into the blood stream
2. the antibodies binds to the tumour antigen
3. The ADC is internalised via endocytosis
4. some of the ADC are released back out of the cell
5. The lysosomes fuse with late endosomes and release the active cytotoxins
6. Cytotoxin interfere with critical cellular machinery

Question 16

What are the problems encountered with ADC

Answer 16

> 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

Question 17

Name some example of an antibody-drug conjugate

Answer 17

Mylotarg
Adcertis
Kadcyla

Question 17

Describe the conjugation of Mylotarg

Answer 17

A CD33 anti-body bound with calitomyocin

Question 18

Properties of Mylotarg

Answer 18

First ADC
Withdrawn and reintroduced with more a new indication
Causes Apoptosis

Question 19

Properties of Kadcyla

Answer 19

EFR-ATK binding antibody
cost £90,000 Per patients

Question 20

What is a biosimilar

Answer 20

A biological medication that is similar to current medication in the market that have the similar but not identical indication