Targeted Therapies (MC) - Block 4

Question 1

What happens when TK activity is dysregulated?

Answer 1

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

Question 2

MOA of TKIs? Problems?

Answer 2

Bind to the ATP binding site of TK

Problems: selectivity for kinases

Question 3

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

Answer 3

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

Question 4

How are TKIs metabolized? ADRs?

Answer 4

CYP3A4 (affected by inducers and inhibitors)

ADR: hepatotoxicity

Question 5

What is the function of VEGF2 inhibitors?

Answer 5

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

Question 6

What is the MOA of sunitinib?

Answer 6

May reduce resistance due to multi-targeting (low selectivity_

Question 7

Describe the instability and ADRs associated with sunitinib?

Answer 7

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

Question 8

What are the VEGF2 inhibitrs?

Answer 8

Sunitinib
Sorafenib

Question 9

What are the B-RAF inhibiotrs?

Answer 9

1. Dabrafenib
2. Vemurafenib

Question 10

Describe the PK of Dabrafenib?

Answer 10

COnverts into 2 active metabolites with loner half-lives

Question 11

Describe the selectvity of vemurafenib?

Answer 11

V600E mutated BRAF inhibition

Question 12

Describe the SAR of EGFR inhibitors

Answer 12

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)

Question 13

What is the mechanism of EGFR?

Answer 13

Activated pathway -> activation of cell growth and proliferation

Inhibits cytotoxicity of anticancer agenr and radiation -> resistance

Question 14

What are the types of EGFR inhibitors?

Answer 14

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

Question 15

What are the ADRs of EGFR inhibitors?

Answer 15

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

Question 16

What makes erlotinib heaptotoxic?

Answer 16

Open para position to the amine

Question 17

What is the ring on gefitinib for? ADR?

Answer 17

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

Question 18

What group is required for HER2 inhibition activity?

Answer 18

Large para group[

Question 19

Describe the structural properties of lapatanib?

Answer 19

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

Question 20

What is unique about afatinib?

Answer 20

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

Question 21

Activity of osimertinib?

Answer 21

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

Question 22

What makes ibrutinib (BTK inhibitor) an irreversible inhibitor?

Answer 22

Michael acceptor

Question 23

What is the indication for Bcr-Abl Inhibitors

Answer 23

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

Question 24

Describe the structure of imatinib?

Answer 24

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

Question 25

Mechanism of resistance towards imatinib

Answer 25

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

Question 26

Describe the structure of nilotinib?

Answer 26

**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

Question 27

PK of nilotinib compared to imatinib?

Answer 27

* 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

Question 28

ADRs of nilotinib?

Answer 28

QT interval prolongation and myelosuppression

Question 29

Structure that contributes to water solubility

Answer 29

Question 30

ADR of dasatanib? Why

Answer 30

Hepatotoxicity from open para amine

Question 31

What cause hepatotoxicity of bosutinib?

Answer 31

Cl gets removed and exchanged for OH

Question 32

How does panatinib overcome T315I resistance?

Answer 32

Acetylene is rigid and linear fitting into binding pocket of mutation Trifluoro methyl increases potency

Question 33

ADR of ponatinib?

Answer 33

Blood clots, hepatotoxcitiy

Question 34

effect of a pyridine ring?

Answer 34

BetterBcr-Abl selectivity

Question 35

Effect of benzamide ring?

Answer 35

PDGFR

Question 36

Effect of piperazine ring?

Answer 36

Water solubility

Question 37

Effect of imidazole ring?

Answer 37

Less resistance from lower pKa

Question 39

Effect of CF3?

Answer 39

Potency

Question 40

Effect of acetylene

Answer 40

Rigid for T315I mutation

Question 41

MOA of leflunomide?

Answer 41

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

Question 42

ADR of leflunomide?

Answer 42

Hepatotoxic (mitochandrial dysfunction

Question 43

What are the overall properties of kinase inhibitors?

Answer 43

1. Not very selective 2. Equiactive metabolites 3. Lipophilic

Question 44

Which of these TKIs would be hepatotoxic?

Answer 44

C and D (open para position to the amine)