Therapeutic targeting Flashcards
Kinases
Bind to ATP
GTPases
Bind to GTP
Sotorasib
Unbinds ras from GTP in pancreatic cancer
How do kinase inhibitors work?
Binds to kinase before ATP can so that the substrate remains dephosphorylated
Allosteric drugs
Binds somewhere else on enzyme and changes shape of binding site
Describe kinase binding
ATP binds to top lobe
Substrate binds to bottom lobe
- Allows hydrolysis
What can clash with the inhibitor if it is too large?
Gatekeeper residue on the beta sheet (ak site)
What can increase the binding strength of the inhibitor?
Additional binding of inhibitor to the hydrophobic sub-pocket
How do kinase inhibitors inactivate kinase structurally?
Kinase is active when parallel to the end loop
(activation loop)
Inhibitors can trap it in an inactive position with the loop out (eg Imatinib)
Kinases and ATP
Gamma phosphate is hydrolysed by kinase and transferred to substrate
Covalent inhibitors
Strong bonds, can’t be displaced
What are the types of kinase inhibitors?
ATP-competitive
Covalent
Allosteric
Mixed
What does BCRABL do?
Form a kinase that shouldn’t exist
Why does chemotherapy affect cancer cells more than normal cells?
Proliferation rate of cancer cells is 100x that of normal cells
Palbociclib
CDK4/6 inhibitor causes G1 arrest”
