Signal Transduction Inhibitors

Question 1

What is the general MOA for the signal transduction inhibitors?

Answer 1

bind to the ATP binding site of tyrosine kinase (not to substrate binding site)

Question 2

What does the drug imatinib target?

Answer 2

Bcr-Abl fusion protein in CML

Question 3

What do erlotinib and geftinib target?

Answer 3

EGFR tyrosine kinase in epithelial driven cancers

Question 4

What are the 3 targets for the drugs imatinib, bosutinib, dasatinib, nilotinib?

Answer 4

bcr-abl, c-kit, PDGF

Question 5

What does datainib target specifically?

Answer 5

Src

Question 6

What is the general resistance mechanism for the signal transduction inhibitors?

Answer 6

change in target proteins (i.e. change in ATP binding site)

Question 7

What are the pharmacokinetics of the signal transduction inhibitors?

Answer 7

oral admin, high plasma protein binding (can be displaced), metabolized in liver (CYP34A)

Question 8

What drugs are used to treat CML?

Answer 8

imatinib, dasatinib, bosutinib, nalotinib; delay death in blast criss

Question 9

What are erlotinib and gefitinib used to treat?

Answer 9

metastatic non-small cel lung cancer (NSCLC) after failure of standard chemo

Question 10

What are the general toxicities for STIs?

Answer 10

n/v, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions; relatively minor

also CHF, mycardial infarction, teratogenic

Question 11

Why do dasatinib, imatinib, nilotinib have more severe STIs?

Answer 11

Abl tyrosine kinases are necessary for normal heart function

Question 12

What are the specific side effects for imatinib?

Answer 12

edema, BM suppression

Question 13

What are the specific side effects for erlotinib and gefitinib?

Answer 13

rare interstitial pneumonia (can be fatal)