Protein Kinase Inhibitors Flashcards
What are protein kinases
It has 2 main subdivisions: tyrosine kinase and serine/threonine kinases
- Catalyses transfer of terminal phos group from ATP to either tyrosine, serine or threonine which regulates the cellular processes proliferation, angiogenesis and invasion
- phosphorylation stimulates a signal cascade
- phosophatase removes phos group which seizes the signalling cascade
- genes coding for protein kinases are mutated in cancer cells
PKI moa
They are competitive mimics of protein kinase
which inhibits phosphorylation
so inhibits signalling cascade
stops uncontrolled proliferation
what is the advantage of PKIs
Each kinase has a unique ATP binding site with highly conserved aa sequence
can use this to develop an inhibitor that binds selectively to one kinase (-nib drugs)
What is the moa of Imatinib
targets Bcr-Abl oncogene in CML patient
- an ATP competitive inhibitor of Abl protein kinase
- CYP3A4 metabolised
SEs = diarrhoea, nausea, rash, myocardial and hepatotoxicity
what are EGFR inhibitors?
it is a tyrosine kinase inhibitor
erlotinib and gefitinib bind reversibly to ATP binding site of EGFR to prevent signalling cascade
the ATP binding site on EGFR is usually unoccupied by ATP as it is a low affinity ligand so drugs can occupy the site
Quinazoline
it is an ATP mimic
occupies triphosphate region of DNA
Lapatinib moa (EGFR and HER2 inhibitor)
inhibits TK activity of the two oncogenes EGFR and her2
binds to ATP binding pocket of EGFR/HER2 PK domain
reduces tumour-causing breast cancer cells
irreversible inhibitor
SEs at high dose = arrhythmia and rash
Pazopanib moa (VEGFR INHIBITOR)
Inhibits VEGFR
blocks tumour growth and inhibits angiogenesis
acts as an ATP mimic
co-administered with CYP3A4 inhibitors
SEs = nausea/vom/diarrhoea, change in hair colour, rash, fatigue, HTN
what do all PKIs do?
mimic ATP
to prevent phosphorylation
and subsequent signalling cascades
