L5-6 Kinases Flashcards
what do all of the kinase inhibitors bind to?
the ATP-binding site of protein kinases
what AA is a common target of several kinases? (slide 19)
tyrosine
what 3 AAs can be phosphorylated and are substrates for kinases and why
Tyrosine
Serine
Threonine
they all have -OH group
what balances the activity of kinases by removing phosphates?
phosphatases - lol
what common step in cell signaling activates kinase activity?
dimerization of something somewhere idk
Types of kinase inhibitors:
Bind to active conformation of the kinase
A. Type I
B. Type II
C. Type III
A
Types of kinase inhibitors:
Bind and stabilize the inactive conformation of the kinase
A. Type I
B. Type II
C. Type III
B
Types of kinase inhibitors:
Occupy an allosteric pocket outside of the ATP-binding pocket
A. Type I
B. Type II
C. Type III
C
Competitive Inhibitors bind kinase in a ________ fashion and therefore must compete with _______ for binding.
reversible
ATP
What type of TKI is gefitinib?
Type I
where does gefitinib bind?
The ATP-binding site of the TK domain of EGFR
EGFR functions through what?
TK activity
EGFR signaling induces what?
cell proliferation
Erlotinib is a small molecule ________ inhibitor of EGFR tyrosine kinase
Reversible
T or F:
Erlotinib is a competitive inhibitor
True, inhibits the enzyme by binding to the ATP binding site in the kinase domain (of EGFR)
Inhibition of kinase activity turns off what?
the signal to proliferate
Gefitinib and Erlotinib are both approved for patients that fall under what criteria?
NSCLC
EGFR exon 19 or 21 mutations
3 common adverse effects of gefitinib and erlotinib
fatigue
rash
diarrhea
Afatinib is a ______ inhibitor of all ____ receptors
covalent**
ErbB
what is Afatinib approved for?
EGFR mutant NSCLC with EGFR mutations (exon 19 and 21)
What is dacomitinib approved for?
non-resistant EGFR mutant lung cancer
what is the main side effect “we should know” from EGFR inhibitors?
skin rash
what mutation causes resistance to gefitinib?
T790M **
Osimertinib:
- A ___ generation EGFR inhibitor
- ______ kinase inhibitor
- Effective against the ____ mutant EGFR
third
covalent
T790M
EGFR forms a heterodimer with ______
HER2 (ErbB2)
HER2 is genomically _____ in breast cancer
amplified
Lapatinib:
- small molecule TKI that blocks _____ and _____ signaling
HER2
EGFR
Lapatinib:
- selective for the treatment of _______ breast cancer
HER2+.
lapatinib:
- currently approved (in combination with capecitabine) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies
advanced metastatic (late stages)
T or F:
Lapatinib is an irreversible inhibitor of both EGFR and HER2
false, reversible
3 common side effects of lapatinib
diarrhea
nausea
vomiting
(also watch for sxs of congestive heart failure for some reason)
Tucatinib:
- small molecule TKI that preferentially binds ____
HER2
Tucatinib:
- selective for the tx of _______ ______
HER2+ breast cancer
lapatinib:
- currently approved (in combination with capecitabine and trastuzumab) for the treatment of ________ ________ breast cancer in pts who have progressed on other therapies
advanced metastatic (sorry same card twice kinda minus the trast drug)
Tucatinib has reduced adverse reactions compared to lapatinib, why is this?
since it is more selective for HER2
Which compounds inhibit EGFR?
A. Gefitinib
B. Osmertinib
C. Afatinib
D. Lapatinib
E. All of the above
E
What mutation in EGFR confers resistance to 1st and 2nd generation EGFR inhibitors?
A. L858R
B. Exon 19 deletion
C. Exon 14 deletion
D. T790M
D
what the fuck is the FLT3 (fms-like tyrosine kinase 3) ligand?
a cytokine receptor important for hematopoietic cell survival and proliferation
FLT3 mutations are found in 30% of what?
acute myeloid leukemia (AML)