Kinase Inhibitors

Question 1

What are the three types of kinase inhibitors (where do they bind)

Answer 1

Type I: binds the active conformation of the kinase
Type II: binds and stabilizes the inactive conformation of the kinase
Type III: occupies an allosteric pocket outside of the ATP-binding pocket

Question 2

What are the common targets of kinases?

Answer 2

Tyrosine, Serine, Threonine

Question 2

What type of inhibiton can kinase inhibitors display (how do they bind)

Answer 2

-competitive inhibitors reversibly bind and compete with ATP for binding
-covalent inhibitors results in blockage of the ATP sit and irreversibly inhibits

Question 3

What are the EGFR targeted kinase inhibitor medications?

Answer 3

Gefitinib (Type 1 TKI)
Afatinib, Neratinib (Covalent Inhibitors)
erlotinib (reversible, competitive inhibitor)

Question 4

What medication was developed to overcome resistance to Gefitinib?

Answer 4

-T790M mutation causes resistance in about 50% of patients taking gefitinib
-Osimertinib (covalent inhibitor)

Question 5

What medications target both EGFR and HER2?

Answer 5

Lapatinib (reversible inhibitor), Tucatinib (favors HER2)

Question 6

What is the mechanism of action for FLT3 inhibitors?

Answer 6

-seen mutated in acute myeloid leukemia (AML)
-mutation can be either an internal tandem duplication or activating mutation in the tyrosine kinase domain

Question 7

What medications are considered FLT3 inhibitors?

Answer 7

midostaurin (broad kinase inhibitor), crenolanib, Quizartinib (specific for ITD mutations)

Question 8

What medications treat the BCR-Abl translocation (chronic myeloid leukemia)?

Answer 8

Imatinib (Gleevec) (Type II inhibitor) inhibits Abl tyrosine kinase
-common “gatekeeper” mutation is T3151 which Ponatinib can inhibit

Question 9

What is the Philadelphia Chromosome?

Answer 9

the translocation to a BCR-ABl gene; Abl is a tyrosine kinase
-this translocation results in chronic myeloid leukemia

Question 10

What is the EML4-ALK translocation?

Answer 10

ALK (receptor tyrosine kinase) can inappropriately fuse with EML4 and become continuously active
-seen in lung cancers

Question 11

What medications treat the EML4-ALK translocation

Answer 11

Alectinib (Alecensa), Brigatinib

Question 12

What is the BRAF mutation?

Answer 12

mutation in the BRAF gene that subs valine (V) in the 600 position to glutamic acid (E)
-seen in melanomas, lung cancers, colorectal cancers

Question 13

What medications treat cancers with BRAF mutations?

Answer 13

Dabrafenib (Tafinlar)
Trametinib (Mekinist) - Type III allosteric inhibitor & can be used w/Dabrafenib
-both medications are not helpful for colorectal cancer

Question 14

What is BTK?

Answer 14

Bruton’s Tyrosine Kinase
-becomes hijacked in B-cell cancers (leukemias, lymphomas)

Question 15

What medications are BTK inhibitors?

Answer 15

Ibrutinib (covalent inhibitor), Acalabrutinib (2nd generation covalent inhibitor; also targets Cys481)

Question 16

What is the mechanism of action of Rapamycin analogues?

Answer 16

Rapamycin = Sirolimus
-inhibits mTOR (a serine-threonine kinase)
-causes immunosuppression (used for organ transplant)

Question 17

What medications are Rapamycin analogues?

Answer 17

Sirolimus, Temsirolimus, Everolimus, Deforolimus