Small Molecule Kinase Inhibitors Part 1

Question 1

Define Tyrosine Kinase

Answer 1

An enzyme that transfer the γ-phosphate group from ATP to a tyrosine residue in a protein (the process known as phosphorylation). This occurs by ATP binding to the enzymatic pocket in the kinase enzyme.

Question 2

Activation of Tyrosine Kinase

Answer 2

o Conversion of the inactive confirmation into the active conformation results in tyrosine kinase activation, which is tightly regulated and essential for normal physiological activity and process. Most of the time the kinase is in the inactive form.

Question 3

What are the mechanisms of Tyrosine Kinase Activation?

Answer 3

Genetic alteration, Gene Amplification, Point mutation, Protein Accumulation, et al.

Question 4

Type 1 Reversible Inhibitors

Answer 4

bind to the active conformation of the kinase with the aspartate residue (white backbone) of the DFG motif pointing into the ATP-binding pocket blocking ATP from binding

Question 5

Type 2 Reversible Inhibitors

Answer 5

bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket

Question 6

Type 3 Reversible Inhibitors

Answer 6

occupy an allosteric pocket that is adjacent to the ATP-binding pocket but does not overlap with it so that ATP cannot bind

Question 7

Type 4 Reversible Inhibitors

Answer 7

bind to an allosteric pocket remote from the ATP-binding pocket making it impossible for it to change from inactive form to active

Question 8

What are the 4 major types of cancers indicated for SMKI

Answer 8

Lung
Breast
Prostate
Colon

Question 9

Chronic Myeloid Leukeimia MOA

Answer 9

Chromosome 9 (abl) and 27 (bcr) fuse to create a new hybrid protein that has high kinase activity that drives leukemia cells to malignancy and proliferation. CML is a single genetic abnormality (one factor = one tumor)
Form: Bcr-Abl kinase

Question 10

Drugs MOA to Treat CML

Answer 10

Competes at ATP binding site on Bcr-Abl protein resulting in inhibition of cell proliferation and induction of apoptosis

Question 11

Drugs Used to Treat CML

Answer 11

Imatinib (gleevec) and Nilotinib (tasigna)

Question 12

Imatinimb Brand and Target

Answer 12

Gleevec

SMKI specific for Bcr-Abl

Question 13

Things that effect Imatinib’s plasma concentration

Answer 13

• Increased plasma concentration by CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin, clarithromycin)
• Decreased plasma concentration by CYP3A4 inducers (rifampin, phenytoin, carbamexapine, phenobarbital, dexamethasone, St. John’s Wort)

Question 14

Imatinib Indication

Answer 14

Newly diagnosed Ph(+) CML
Acute Lymphoblastic Leukemia (ALL)
GI Stromal Tumor (GIST)

Question 15

Imatinib Drug Inteactions

Answer 15

Should us LMWH or heparin NOT warfarin

Should be aware that acetaminophen increases exposure when used with Gleevec

Question 16

Imatinib AE

Answer 16

• Fluid retention and edema (watch weight)
• Hematologic toxicity (anemia, neutropenia, thrombocytopenia)
• Hepatoxicity
• Severe CHF and left ventricular dysfunction (LVD)
• Hemorrhage

Question 17

Imatinib Monitoring Ph(+) CML after Treatment

Answer 17

• Hematologic test (normal range of blood cell counts)
• Cytogenetic test (number of cells with Ph+ chromosome)
• Molecular tests (existence of Ph+ DNA/mRNA)

Question 18

Nilotinib Brand and Target

Answer 18

Tasigna

SMKI specific for Bcr-Abl

Question 19

Nilotinib Indication

Answer 19

Chronic or accelerated Ph(+) CML in adult patient who are resistant/intolerant to imatinib

Question 20

Nilotinib Clinical Pearls

Answer 20

• Effectiveness in based on hematologic and cytogenetic response rates
• Do NOT use in patients with hypokalemia, long QT syndrome or hypomagnesemia!!!

Question 21

Nilotinib AE

Answer 21

• QT prolongation and sudden deaths
• Myelosuppresion (thrombocytopenia, neutropenia and anemia)
• Elevated serum lipase (pancreatitis)
• Hepatotoxicity
• Electrolyte abnormalities (low Ph, K, Ca, Na, and high K)