topic 20 - Cancer 2 Flashcards
what is gemcitabine?
Gemcitabine is phosphorylated in vivo and incorporated into DNA to create faulty DNA which cannot be repaired, resulting in cell death.
It is given intravenously for a variety of cancers in combination with other drugs.
what is 6-mercaptopurine?
6-Mercaptopurine also gets transformed into nucleoside triphosphates and incorporated into DNA, causing cell death by impeding various enzymes
Typically used for acute leukaemias, being more effective in children.
what is raloxifene? hormone receptors
Raloxifene binds more strongly than estradiol
Extra H-bond stops H12 helix moving into right position for signal transduction
what are kinase inhibitors?
Kinases are enzymes which perform phosphorylation reactions on Ser, Thr, Tyr.
Changes structure + function of the phosphorylated protein.
Phosphorylation is often used to activate another kinase.
Signal transduction from receptors to the nucleus.
what do kinase inhibitors target?
Kinases use ATP as phosphate source
Despite all kinases using ATP, many selective inhibitors discovered for ATP binding pocket.
what are the 4 types of kinase inhibitors?
type 1 - drug binds active conformation
type 2 - drug binds inactive connfromation
type 3 - drug binds nearby hydrophobic pocket
type 4 - drug binds elsewhere (allosteric)
design of kinase inhibitors
Certain breast, lung, and other cancers overexpress EGFR.
Gefitinib is a Type I inhibitor of EGFR. Its structure was modified from the lead compound to get around metabolic problems.
The end result binds the kinase region of EGFR less strongly than the lead, but because it is biostable, it works better. It is also orally available.
what is Raf?
Raf is a kinase activated by protein-protein interaction with Ras. The most common oncogenic mutation V600E present in 8% of all human cancers, leaves it constantly active.
New Raf inhibitors produced by rigidification of prior hit – increases selectivity for specific kinases and binding strength by reducing entropic penalty of adopting the bound conformation.
allosteric kinase inhibitors
Protein kinase B (also known as Akt) is responsible for cell survival and growth. Overexpressed in pancreatic, breast, and ovarian cancer.
Intended for combination therapy to fight resistance
Phase I trials successful – no unacceptable side effects
Phase II trials registered
mutations in Ras proteins - kinase inhibtors
Mutations in Ras proteins drive over 30% of cancers. The protein must be membrane bound to perform its job. This happens through a farnesyl posttranslational modification catalysed by farnesyl transferase (FTase)
Use peptide as basis for developing FTase inhibitor: remove hydrolysable amides; increase hydrophobicity with ester; biostability with sulphone
Does inhibit FTases, but cells attach a different hydrophobic chain instead – cannot inhibit that enzyme without serious side effects.
