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61 Cards in this Set

  • Front
  • Back
What do kinases do?
add phosphate from ATP to proteins
What 3 amino acids do kinases phosphorylate?
Ser, Thr, Tyr
Which form of kinase does Gleevec bind? (active/inactive)
inactive (blocks ATP binding site)
What are the 3 drugs that target abl?
Gleevec, Dasatinib, nilotinib
What is the target of Iressa?
EGFR inhibitor
What are the targets of Sutenet? (4)
c-Kit, VEGFR, PDGFR, FLT3
Which anti-cancer drug was taken off the market?
Iressa
What is Vandetanib approved to treat?
thyroid cancer
What is Vemurafenib approved to treat?
metastatic melanomas (BRAFV60E)
Which drug needs testing for BRAF-V60E?
Vemurafenib
Venurafenib aka
Zelboraf
Vandetanib aka
Caprelsa
What is Ruxolitinib approved to treat?
melofibrosis, a myeloprofilerative neoplasm
What does Vandetanib target?
VEGFR, EDFR (RET-Tyrosine kinsase)
MOA of Vemurafenib?
B-Raf/MEK/ERK pathway inhibitor
MOA of Ruxolitinib?
inhibits JAK1 and JAK2
What is Crizotinib approved to treat?
last state non-small cell lung cancer
What is Axitinib approved to treat?
2nd line treatment for renal cell carcinoma
MOA of Crizotinib?
inhibits Anaplastic lymphoma kinase (ALK)
MOA of Axitinib?
Inhibits VEGFR-1, VEFGR-2, VEGFR-3, PDGFR and c-Kit (broad spectrum)
What dictates how ATP is bound by kinases?
C-helix
When inactive can DFG bind Mg?
NO
What is the amino acid corresponding to the "D" in DFG?
Asp
What does the Asp in DFG bind?
Mg (in the active form)
When inactive, which part of DFG binds inhibitors?
F
2 consequences of inactive orientation of the C-helix
1. lack of binding interaction involving glu-lys-phos & 2. provides a pocket for inhibitor groups
What is the counter ion for the ATP triphosphate?
Mg
When active, can DFG bind Mg?
Yes (not when inactive and the D is pointing away from the pocket)
Where do most kinase inhibitors work?
At the ATP binding site (except Temsirolmus)
What does Temsirolimus bind to?
FK506 binding protein 12
What does temsirolimus inhibit?
mTOR (activated in tumor cells)
Which drug binds the substrate, not the ATP binding site?
Temsirolimus (because it is too big)
What does the Philadelphia chromosome have a gene encoding for?
a CML fusion protein
What type of kinase is BCR?
Ser/Thr kinase
What type of kinase is ABL?
Tyrosine kinase
What type of kinase is the fusion protein?
Tyrosine kinase
What does the fusion protein consist of?
bcr-abl
What is the mechanism of the Philadelphia chromosome formation?
reciprocal translocation between chromosomes 9 and 22
What kind of activity does the bcr-abl fusion protein have?
Constitutively active
Gleevec
Imatinib
What is the MOA of gleevec?
Tyrosine kinase inhibitor, binds ATP binding site of AB, **inhibits the inactive form
What does gleevec treat?
CML- chronic myelogenous leukemia
Why were dasatinib and nilotinib developed?
for pts resistant or unresponsive to gleevec
The majority of critical mutations to BCR/ABL make the ABL domain _______(inactive/active)
active (which is why gleevec won't work)
T/F most mutations in bcr/abl map to drug contact residues
FALSE
What are two drugs used as alternatives to gleevec?
Dasatinib, Nilotinib
Does a lower or higher IC50 mean the drug is more potent?
lower
What is the critical mutation in the brc/abl region?
T315A
What does T315A mean for binding/structure?
Threonine--> alanine, abolishes a critical association with gleevec
Is Ala or The in the active conformation of bcr-abl?
Ala
What molecule provides for the steric clash between dasatinib and active site?
bound water
What are other targets of Gleevec besides bcr-abl? (4)
KIT, PDGFR, NQO2, V-ATPas
What could you treat by inhibiting KIT?
GIST (gastrointestinal stromal tumors), sMC
What could you treat if you inhibit PDGFR? (3)
CEL, SSc, stroke
What could you treat if you inhibit NQ02? (2)
Fibrosis, inflammation
What are the two differences between the inactive and active conformations of kinases?
1) Orientation of the C-helix
2) Conformation of the DFG tripepide
What kinases do dasatinib target?
abl , c-Kit, PDGFR, Src
What kinases do nilotinib target?
abl , c-Kit, PDGRFb, Src, Ephthrin
What three kinase inhibitors target abl?
Gleevec, dasatinib, nilotinib
What are some of the future users of gleevec and other kinase inhibitors? (4)
wider breadth of anti-cancer drugs, antiagniogenics, bone building/anti-osteoprosis, inflammation diseases
What are the two anti-angiogensis kinase inhibitors?
Sutent and Iressa