Small Molecule Kinase Inhibitors Part 1 Flashcards
Define Tyrosine Kinase
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.
Activation of Tyrosine Kinase
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.
What are the mechanisms of Tyrosine Kinase Activation?
Genetic alteration, Gene Amplification, Point mutation, Protein Accumulation, et al.
Type 1 Reversible Inhibitors
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
Type 2 Reversible Inhibitors
bind and stabilize the inactive conformation of the kinase with the flipped aspartate residue facing outward of the binding pocket
Type 3 Reversible Inhibitors
occupy an allosteric pocket that is adjacent to the ATP-binding pocket but does not overlap with it so that ATP cannot bind
Type 4 Reversible Inhibitors
bind to an allosteric pocket remote from the ATP-binding pocket making it impossible for it to change from inactive form to active
What are the 4 major types of cancers indicated for SMKI
Lung
Breast
Prostate
Colon
Chronic Myeloid Leukeimia MOA
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
Drugs MOA to Treat CML
Competes at ATP binding site on Bcr-Abl protein resulting in inhibition of cell proliferation and induction of apoptosis
Drugs Used to Treat CML
Imatinib (gleevec) and Nilotinib (tasigna)
Imatinimb Brand and Target
Gleevec
SMKI specific for Bcr-Abl
Things that effect Imatinib’s plasma concentration
- 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)
Imatinib Indication
Newly diagnosed Ph(+) CML
Acute Lymphoblastic Leukemia (ALL)
GI Stromal Tumor (GIST)
Imatinib Drug Inteactions
Should us LMWH or heparin NOT warfarin
Should be aware that acetaminophen increases exposure when used with Gleevec
Imatinib AE
- Fluid retention and edema (watch weight)
- Hematologic toxicity (anemia, neutropenia, thrombocytopenia)
- Hepatoxicity
- Severe CHF and left ventricular dysfunction (LVD)
- Hemorrhage
Imatinib Monitoring Ph(+) CML after Treatment
- Hematologic test (normal range of blood cell counts)
- Cytogenetic test (number of cells with Ph+ chromosome)
- Molecular tests (existence of Ph+ DNA/mRNA)
Nilotinib Brand and Target
Tasigna
SMKI specific for Bcr-Abl
Nilotinib Indication
Chronic or accelerated Ph(+) CML in adult patient who are resistant/intolerant to imatinib
Nilotinib Clinical Pearls
- Effectiveness in based on hematologic and cytogenetic response rates
- Do NOT use in patients with hypokalemia, long QT syndrome or hypomagnesemia!!!
Nilotinib AE
- 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)
