9 - Kinase Inhibitors Flashcards
1
Q
what is the general naming convention for kinase inhibitors?
A
drugs end in -inib
(for inhibition)
2
Q
how are kinases involved in signal transduction?
A
signal transduction occurs by phosphorylation
a kinase ADDs a phosphate group –> can activate/ or inactivate
phosphatase REMOVES a phosphate group –> can activate/ or inactivate
3
Q
post-translational phosphomodification:
structural and functional consequences
A
- addition of phosphate group to the R side chain can dramatically change the conformation of the protein
- will directly affect function
- negative side chains are present w/ the phosphorylation; charge repulsion (charge-charge interaction w/in one side chain of the amino acid)
4
Q
imatinib:
common name; biochem, mech, target
A
- aka Gleevac; first kinase inhibitor developed (1990s) w/ great results
- biochem: small molecule;
- mechanism of inhibition:
- Imatinib is a competitve inhibitor (active site may be small), blocking active site
- prevents phosphorylation of the kinase substrate by ATP
- target: BCR-Abl tyrosine kinase,
- fusion protein arising from translocation b/w chromosome 9 & 22 (Abl1 gene on 9, to BCR “breakpoint cluster region” on 22)
- which exists ONLY in cancer cells (not healthy cells)
Very expensive tx (up to $100,000 per year)
5
Q
imatinib:
mech of action
A
- Imatinib is a competitve inhibitor (active site may be small), blocking active site
- substrate cannot enter kinase site
- prevents phosphorylation of the kinase substrate by ATP
- tumor cell cannot proliferate
6
Q
imatinib:
indications
A
- Inhibits other receptor tyrosine kinases for c-kit and PDGF (platelet derived growth factor)
-
First line tx: in chronic phase CML (chronic myelogenosu leukemia) in blast crisis-
- CML = a pluripotent hematopoietic stem cell disorder w/ t(9:22) philadelphia chromosomal translocation
- Second line tx: for chronic phase CML that has progressed on prior interferon-alpha
- Also tx:
- gastrointestinal stromal tumors (expressing c-kit tyrosinase kinase)
- ^ ex. of personal therapy
7
Q
imatinib:
absorption, metabolism, and toxicity
A
- absorbed: orally
- metabolized: in liver
- toxicity:
- acute: Nausea/vomiting
- chronic: fluid retention w/ ankle and periorbital edema, diarrhea, myalgias, congestive heart failure
8
Q
imatinib:
how does resistance occur?
A
Two possible mechanisms can result in resistance to Imatinib:
- BCR/ABL kinase domain mutations –>
- Change in structural gene sequence which changes protein structure
- But no change in gene number
- Imatinib no longer recognized
- BCR/ABL gene amplification and over-expression
- Change in gene number
- But no change in gene protein
- Imatinib dose not sufficient to inhibit enzyme (and you can’t increase the dose to compensate for the gene amplification w/out causing toxicity)
9
Q
dasatinib:
how does it differ from Imatinib?
A
- binds to BOTH the active and inactive conformations of the Abl kinase domain
- oral inhibitor of several tyrosine kinases, (incl. BCR-Abl, Src, c-kit, adn PDGFR-alpha
- mutations in BCR-Abl kinase (due to changes in structural gene) –> allowing it to overcomes imatinib resistance
- indicated for CML and Ph chromosome-positive ALL – which are also imatinib resistant
- Philadelphia (Ph) chromosome-positive lymphoblastic leukemia (ALL)
10
Q
nilotinib:
key characteristics
A
- Second-generation (better inhibitor) phenylamino-pyrimidine molecule
- Inhibits tyrosine kinases: BCR-Abl, c-kit, and PDGFR-beta
- Higher binding affinity (up to 20- to 50-fold) for the ABL kinase when compared w/ imatinib
- BCR-Abl mutations –> allows it to overcome imatinib resistance
- Indicated for:
- chronic phase and accelerated phase CML w/ resistance
- first-line therapy of chronic phase CML (chronic myelogenous leukemia)
11
Q
bosutinib:
key characteristics
A
-
potent inhibitor of the BCR-Abl tyrosine kinase
- (of note, when treating w/ Gleevac –> may induce a mutation)
- retains activity in 16 to 18 imatinib-resistant BCR-Abl mutations (Personal therapy - can measure mutations in patients)
- Indicated for tx:
- adult patients w/ chronic, accelerated, or
- blast phase Ph chromosome positive CML w/ resistance or intolerance to previous therapy
12
Q
growth factor receptor inhibitors:
(general) metabolism, side-effects
A
- metabolism: in the liver, mostly by the CYP3A4 liver microsomal enzyme
- side-effects:
- potential drug-drug interactions w/ other drugs metabolized by the CYP3A4 system –> can change the specificity of the drug/ affecting its functions
- grapefruit – contains lipid lowering componds
- st. john’s wort
13
Q
erlotinib:
function, adverse effects
A
- fxn:
- inhibitor of tyrosine kinase domain assoc. w/ the EGFR (epidermal growth factor receptor)
- ( you can form the inhibitor/receptor complex, but you can’t proceed/form the enzyme+product complex)
- adverse events:
- acneiform skin rash - (acne-like rash)
- diarrhea
- anorexia
- fatigue
14
Q
erlotinib:
indications, and drug-drug interactions
A
- indications: **need to try other drugs first
- personal therapy: first-line tx of metastatic non-small cell lung cancer (NSCLC)
- pts whose tumors have EGFR exon 19 deletions, or exon 21 (L858R) mutations and are refractory to at least 1 prior chemo regimen
- maintenance therapy for pts w/ metastatic NSCLC
- combination chemo w/ gemcitabine for the tx of advanced pancreatic cancer
- personal therapy: first-line tx of metastatic non-small cell lung cancer (NSCLC)
- drug-drug interactions:
- metabolized in the liver by CYP3A4 enzyme system
- drugs of concern
- phenytoin
- warfarin
- grapefruit products
- st. john’s wort
15
Q
sorabenib:
key characteristics (purpose, mech, indications)
A
- purpose: if you can inhibit the kinases – you can inhibit the vascular growth by starving/inhibiting tumor
- mechanism:
- inhibits multiple receptor tyrosine kinases
- (VEGF-R2 and VEGF-R3)
- tx:
- advanced renal cell cancer
- advanced hepatocellular cancer
KC: TRY THE CLASSICAL CHEMO AGENTS FIRST
