Modern Chemotherapy Flashcards
What is a Nib?
Tyrosine Kinase inhibitors
What is a Rib (THINK R)?
PARP inhibitors
What does PARP stand for?
Poly(ADP)ribose Polymerase
Name a PARP inhibitor.
Olaparib
Name a Tyrosine Kinase inhibitor.
Imatinib
What does PARP do?
It fixes single strand breaks in DNA (e.g. those caused by Topoisomerase I).
What genes do PARP inhibitors target?
BRCA 1 & 2
What do healthy BRCA 1 & 2 genes do?
They produce proteins that are involved in the repair of double strand breaks in DNA.
What happens if PARP is inhibited?
The single strand breaks in DNA cannot be repaired. This damage is carried forward through proliferation and leads to double strand breaks. These can either be repaired by homologous recombination or apoptosis occurs.
How does Olaparib work?
It is a competitive inhibitor of NAD+ and the BER pathway. This inhibition causes an accumulation of single strand breaks, which leads to a further accumulation of double strand breaks. BRCA that is faulty cannot repair these breaks and therefore the tumour cells become genomically unstable and undergo cell death.
What influenced Olaparib development?
The cyclopropylamide group in Olaparib increased its oral bioavailability. Its metabolic conversion into a piperazine increased both cell permeability and potency.
What does CML stand for?
Chronic myelogenous leukaemia
Name a BRAF inhibitor.
Sorafenib, Vemurafenib, Dabrafenib
How might resistance arise to Tyrosine Kinase inhibitors?
Upregulation of other growth related tyrosine kinases, or site mutations in the binding site of the target kinase.
For example, a T790M mutation at an EGFR receptor in Lung Cancer can reactivate the pathway which prevents TKI binding.
How was Imatinib developed?
It was developed from a lead molecule (2-phenylaminopyrimidines) with low potency and low selectivity as a kinase inhibitor. Addition of p-methyl group on aromatic ring introduced ABL kinase activity. Introduction of piperazine offered water solubility.
