DNA Repair enzyme inhibitors

Question 1

How does DNA repair itself?

Answer 1

Two DNA damage response pathways

• If repair pathway B is eliminated (e.g., by smoking) this
• leads to genome instability which creates a cancer cell
• repair pathway A is still active which keeps the cancer cell alive
• inhibitor blocks A so cancer cell dies

Question 2

What is DNA dependent protein kinase?

Answer 2

An enzyme that plays key role in non-homologous end joining (NHEJ) pathway of DNA double strand break repair by recruiting repair proteins

Question 3

What is the moa of DNA dependent protein kinase inhibitors (DNA-PKIs)?

Answer 3

it is given in combo with another agent to enhance effect of agent by preventing cell from repairing the damage caused
promotes cell death
it can also sensitise cells to radio and chemotherapy

Question 4

what is PARP?

Answer 4

A DNA repair enzyme that plays a key role in DNA base excision repair pathway (BER)
- and uses NAD+ as a substrate rather than a coenzyme
on PARP there is a DNA binding domain at one end
and an NAD+ catalytic domain at other end
ADP ribose fragment binds enzyme at NAD+ end which polymerises it and allows DNA to be repaired

Question 5

What is the moa of PARP inhibitors

Answer 5

They mimic PARP enzyme
so that ADP ribose fragment binds to inhibitor instead of PARP
so fragment cant be polymerised
DNA cant be repaired
it can also sensitise cells to radio and chemotherapy

Question 6

Give examples of PARP inhibitors

Answer 6

Nicotinamide 
Benzamide derivatives
Pyrazine-2-carboxamide
Xanthines 
Chromenones

Question 7

Give examples of DNA PKIs

Answer 7

AZD-7648

Question 8

What are the characteristics of 1st gen PARP inhibitors?

Answer 8

Common benzamide group
poor specificity at required inhibitor conc
low micromolar competitive inhibitors at NAD+ domain