Modern Chemo WS W9 Flashcards

1
Q

Learn the functional group

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Explain how a PARP inhibitor can be active as a single agent in BRCA1 and BRCA2 deficient cancers

A

BRCA 1and 2 are tumor suppressor genes and help repair DSBs

PARP is an enzyme involved in repairing SSBs

PARP in BRCA deficient cells:
- PARP is inhibited = SSB becomes DSB = no functional BRCA = no HR repair = DNA damage builds up = cell dies

PARP inhibition alone isnt lethal and BRCA loss alone isnt lethal but together = cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Describe the bcr-abl mutation.

A

Fusion gene

Parts of BCR (chromo 22) and ABL (chromo 9) are joined due to chromosomal translocation

creates a constitutively active tyrosine kinase, meaning It’s always “on”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Considering imatinib is a kinase inhibitor, how might resistance develop to imatinib

A

primary resistance (doesn’t work from the start) and acquired resistance (works at first, then stops).

  1. Point mutations in the domain - mutations alter the binding site so imatinib can no longer bind effectively
  2. Amplification of BCR-ABL gene - more BCR-ABL is made which overwhelms imatinibs effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Vemurafenib is the first selective BRAF inhibitor. It can selectively inhibit the cancerous BRAF
mutation V600E over the wild type.
a. Describe the interactions Vemurafenib could make with glutamic acid (E) that could
not be made with valine (V).

A

Interactions that can be made with E that it cant with V:

H bonding
- E has a carboxly group that can act as a HBA

Ionic interactions
- The negative charge on E sidechain conform electrostatic attractions

Induced fit or altered binding pocket
- The larger polar side chain of E might reshape the binding pocket creating new interaction sites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

b. Describe two common resistance mechanisms to tyrosine kinase inhibitoRS

A
  1. Mutations in the kinase domain.
  2. Activation of alternative signalling pathways.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

C. Dabrafenib can target the cancerous BRAF mutations V600E and V600K, but
Vemurafenib is only effective against the mutation V600E. Describe the likely
resistance mechanism BRAF V600K demonstrates towards Vemurafenib, and why
this amino acid change would provide resistance.

A

They are both activating mutations in the BRAFG and substitute valine with:
- E in V600E
- K in V600K

Vemurafenib was designed by specifically to BRAF V600E mutant protein and it’s binding pocket forms favourable interactions

Why is V 600 K resistant to Vemurafenib

  1. Charge reversal
    - Glutamic acid is negatively charged while lysine is positively charged
    - Vemurafenib Structure is to interact with a negatively charged residue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Why are PARP inhibitors and DNA alkylators prescribed together?

A

DNA alklators
- Add alkyl groups to DNA bases → causes DNA damage, especially single-strand breaks (SSBs) and crosslinks.

PARP inhibitors
- block PArP enzymes,es that normally help with SSB repair

Why combine them?
- DNA alkylators create initial damage.
PARP inhibitors block the repair, making that damage more severe and persistent.
Result: More DSBs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly