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