Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Drug Action IV > Targeted Therapies (MC) - Block 4 > Flashcards

Targeted Therapies (MC) - Block 4 Flashcards

1
Q

What happens when TK activity is dysregulated?

A

Accelerate cell signalingcascades and cellular growth, induce tumors, and augment antiapoptotic processes

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

MOA of TKIs? Problems?

A

Bind to the ATP binding site of TK

Problems: selectivity for kinases

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

What is the difference between type 1 and 2 TK inhibitors?

A

Type 1: bind to active conformation of kinase
Type 2: bind to inactive conformation (more selctive)

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

How are TKIs metabolized? ADRs?

A

CYP3A4 (affected by inducers and inhibitors)

ADR: hepatotoxicity

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

What is the function of VEGF2 inhibitors?

A

Inhibits angiogenesis of tumors and keeps nutrients from supproting growth
* Decreased permeability of tumor cell vasculature easing delivery of chemo agents

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

What is the MOA of sunitinib?

A

May reduce resistance due to multi-targeting (low selectivity_

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the instability and ADRs associated with sunitinib?

A

Conjugated -> yellow can be transferred to skin and bodily fluid

Keep away from light
* Z isomer is more potent than E
* Light convert Z to E -> in the dark it will return to Z

HTN

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the VEGF2 inhibitrs?

A

Sunitinib
Sorafenib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the B-RAF inhibiotrs?

A
  1. Dabrafenib
  2. Vemurafenib
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the PK of Dabrafenib?

A

COnverts into 2 active metabolites with loner half-lives

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Describe the selectvity of vemurafenib?

A

V600E mutated BRAF inhibition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the SAR of EGFR inhibitors

A

Pharmacophore: quinaoline ring (Nitrogens are essential for activity)
EWG (Cl): meta position for good selectivity
Larger para sub (F): bind to inactive confomration (Type 2) and HER2 (lipophillic pocket)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the mechanism of EGFR?

A

Activated pathway -> activation of cell growth and proliferation

Inhibits cytotoxicity of anticancer agenr and radiation -> resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the types of EGFR inhibitors?

A

1st: Reversible -> erlotinib, gefitinib
2nd: irreversible (selective for inactive) -> afatinib
3rd: mutant selective -> osimertinib

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the ADRs of EGFR inhibitors?

A

Macropapular skin rash correlated with therapeutic effects (worsens in sunlight)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What makes erlotinib heaptotoxic?

A

Open para position to the amine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the ring on gefitinib for? ADR?

A

For water solubility

ADR:
* Hepatotoxicity: reactive metabolite can also be formed in lungs (CYP1A1) -> smokers generate more of metabolite
* Metabolite can also cause ftal interstitial lung disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What group is required for HER2 inhibition activity?

A

Large para group[

19
Q

Describe the structural properties of lapatanib?

A

Sulfur is for water solubility
Ether are metabolized to OH (prodrug) -> can cause hepatotox from OH in para to amine -> given at much higher doses

20
Q

What is unique about afatinib?

A

Amine: water solubility
Michale acceptor: irreversible inhibitor (formation of covalent bonds) of Type 2 and HER2 (large para group)

21
Q

Activity of osimertinib?

A

Contains a Micheal acceptor -> irreversible inhibitor
* Cardiotox (QT prolongation and cardiomyopathy)

22
Q

What makes ibrutinib (BTK inhibitor) an irreversible inhibitor?

A

Michael acceptor

23
Q

What is the indication for Bcr-Abl Inhibitors

A

CML involving Philadelphia chromosomal trnaslocation (Bcr-Abl fusion: the causitive agent for CML)

24
Q

Describe the structure of imatinib?

A

Benzanine group: Not selective because of inhibition of PDGFR kinase -> fluid retenton
Piperazizne ring: wter solubility
Puridine ring: Bcr-Abl selectivity

25
Q

Mechanism of resistance towards imatinib

A

T315I mutation: gatekeeper to hydrophobic binding pocket and Ile is large blocking access to receptor

26
Q

Describe the structure of nilotinib?

A

Benzanine group: Not selective because of inhibition of PDGFR kinase -> fluid retenton
Imidazole: wter solubility
Puridine ring: Bcr-Abl selectivity
Tri-fluoro methyl: Increase potency

27
Q

PK of nilotinib compared to imatinib?

A
  • Lower F but can increase with high fat meals (increases toxicity)
  • Less resistance due to imidazole ring (lower PKa) -> not a substrate for organic cation tansporter 1 protein (OCT1P1) -> gets imatinib into cells but contributes to resistance
28
Q

ADRs of nilotinib?

A

QT interval prolongation and myelosuppression

29
Q

Structure that contributes to water solubility

A
30
Q

ADR of dasatanib? Why

A

Hepatotoxicity from open para amine

31
Q

What cause hepatotoxicity of bosutinib?

A

Cl gets removed and exchanged for OH

32
Q

How does panatinib overcome T315I resistance?

A

Acetylene is rigid and linear fitting into binding pocket of mutation

Trifluoro methyl increases potency

33
Q

ADR of ponatinib?

A

Blood clots, hepatotoxcitiy

34
Q

effect of a pyridine ring?

A

BetterBcr-Abl selectivity

35
Q

Effect of benzamide ring?

A

PDGFR

36
Q

Effect of piperazine ring?

A

Water solubility

37
Q

Effect of imidazole ring?

A

Less resistance from lower pKa

38
Q
A
39
Q

Effect of CF3?

A

Potency

40
Q

Effect of acetylene

A

Rigid for T315I mutation

41
Q

MOA of leflunomide?

A

Anti-inflammatory and immunosuppressive
* High doses: inhibits protein tyrosine kinase (PDGF)

42
Q

ADR of leflunomide?

A

Hepatotoxic (mitochandrial dysfunction

43
Q

What are the overall properties of kinase inhibitors?

A
  1. Not very selective
  2. Equiactive metabolites
  3. Lipophilic
44
Q

Which of these TKIs would be hepatotoxic?

A

C and D (open para position to the amine)

Drug Action IV (28 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions