Lec 18- Targets: Kinases Flashcards
1
Q
The Philadelphia chromosome
A
- Reciprocal translocation between chromosome 9 and 22 forms an extra long chromosome 9 (der9) and the Philadelphia chromosome containing abl and bcr genes fused together
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2
Q
Glivec
A
- Imatinib mesylate- Glivec
- Inhibitis Bcr-Abl tyrosine kinase
- Inhibits proliferation & induces apoptosis in Philadelphia chromosome positive CML cells (and other leukeamias)
- Not entirely selective, but side effects are mild
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3
Q
Glivec
Inhibits mesylate
A
4
Q
Kinases as targets in signalling pathways
A
- Receptors- cell membrane- signal transducer
- Receptor cause cascade of reactions
- They change gene transcription turn on genes responsible for that signal response
- Processes are regulated by kinases
- We can be selective to identify targets responsible for causing a negative response- inhibit the target inhibit the process
5
Q
Kinases families
A
6
Q
Kinases and phosphatases
A
- Kinase take ATP (terminal phosphate on ATP) and adds it to the OH group of a protein
- This is usually a way to activate the protein- turn on growth/activation
- Phosphates take phosphate off returning protein to the basal state
- AA= Serine /Threonine (enzymes bad at distinguishing the 2 so do both), Tyrosine, Histidine
- We ensure that we only get activation when required by having increased levels of phosphatase and low levels of the kinase (cell is off)- prevent necessary growth
- We either increase kinase or decrease phosphatase to turn on- upregulation of kinase is the more common mechanism
7
Q
Receptor tyrosine kinases (RTK)
A
- Receptor => ligand binding (eGF) => intracellular- part that turns on pathway
- Activated receptor recruits other proteins e.g. adaptors (Grb, SOS)
- These recruit other proteins and activate them (e.g. kinases)
- Kinases phosphorylate downstream targets- activates them
- On activation the dimers of the receptor transphosphorylate
- This activates the receptor and turns on downstream signalling
- Phosphatase activity dephosphorylates
- Desensitization (interalisation) also reduces signalling
8
Q
RTK- potential targets
A
- Prevent hormone binding to the receptor(the drug doesn’t have to cross the cell membrane)
- Prevent phosphorylation of RTK
- prevent ATP
- Prevent transphosphylation of the receptor
- Prevent the recruitment of adaptors
9
Q
RTK downstream signalling
MAPK pathway
A
- Proliferation
- Cell cycle
- Differentiation
- Transformation
- Survival (apoptosis)
- Cytoskeleton
- Adhesion
- Motility
- And other
10
Q
Receptor tyrosine kinases downstream signalling
A
- Receptor activates and recruits proteins
- Ras adds phosphate to Raf
- Raf phosphorylates MEK
- MEK phosphorylates ERK
- Erk activates proteins in nucleus responsible for gene transcription
- Many different enzymes. 1 enzyme can catalyse many enzymes = cascade = amplification of signalling event
- MAPK pathway has lots of effects
11
Q
Biochemical basis of biological decision making
A
- Model of decision making using cells
- Treatment with epidermal growth factor (EGF) encourages growth
- Treatment with Nerve growth factor (NGF) causes irreversible changes (differentiation)
12
Q
Cell cycle inhibitors
A
- Mostly serine-threonine kinases
- Cyclin-dependent kinases
- Growth
- DNA synthesis- most common to have mutations, this is often disrupted leading to mutations and excessive growth
- Lose ability to identify damaged DNA, often allowed through chekcpoints with damaged DNA
- Growth and preparation for mitosis
- Mitosis
13
Q
Intracellular inhibitors
A
- Small molecule inhibitors of the EGFR TK domain
- Most developed are anilinoquinazolines
- A number of pharma companies have adopted this strategy
- One additional ATP-competitive TK inhibitor is that being developed by Novartis, named PKI 116, based on a parental pyrrolopyrimidine structure
14
Q
Examples
A
