Protein Kinase Inhibitors

Question 1

What are protein kinases?

Answer 1

Involved in cell signalling processes
2 main sub-divisions = tyrosine + serine/threonine
Catalyse the transfer of terminal phosphate group from ATP to tyrosine/serine/threonine
Phosphorylation induces responses + stimulates a signal cascade
Remove phosphate = cascade ceases

Question 2

Describe protein kinases in cancer therapy

Answer 2

Targeted cancer therapy
Genes coding these proteins = mutated in cancer cells
STOP cascade = prevents uncontrolled proliferation
Each kinase has unique ATP binding domain = the differences utilised to develop inhibitor

Question 3

How are abnormal protein kinases in cancer mediated?

Answer 3

Gain of function mutations
Genomic amplification
Chromosomal rearrangements
Autocrine activation

Question 4

Describe the MoA

Answer 4

Inactive receptor tyrosine kinase (RTK)
Kinase activity stimulated through dimerised RTK
RTK is activated via autophosphorylation
Signal relayed by activated signalling proteins into the cell’s interior

Question 5

Describe Imatinib

Answer 5

ATP competitive inhibitor of Abl protein kinases
Chronic myelogenous leukaemia
CYP metabolism
SE = diarrhoea, nausea, rash, myocardial + hepatoxicity

Question 6

Describe EGFR

Answer 6

Epidermal growth factor receptor
Highly expressed + mutated in cancer
Tyrosine kinase

Question 7

Describe Erlotinib + Gefitinib MoA

Answer 7

Bind irreversibly to ATP binding site of EGFR to prevent signalling cascade

Question 8

Describe Erlotinib properties

Answer 8

Non-small cell lung cancer
CYP metabolism
SE = hepatoxicity + rash SE

Question 9

Describe Gefitinib properties

Answer 9

Single agent in platinum/docetaxel refractory NSCLC
CYP metabolism
SE = rash, diarrhoea, pneumonia, pulmonary fibrosis, corneal ulceration + aberrant eyelash growth

Question 10

Describe Lapatinib MoA

Answer 10

Inhibits tyrosine kinase activity of oncogenes EGFR + HER2
Inhibits receptor signal processes by biding to ATP-binding pocket of EGFR/HER2 protein kinase domain
Pseudo-irreversible inhibitor

Question 11

Describe Lapatinib properties

Answer 11

In combo with Capecitabine as 2nd line (post anthracycline, taxane + trastuzumab)
HER2 positive breast cancer
CYP metabolism
SE = high doses = arrhythmia + rash

Question 12

Describe Pazopanib MoA

Answer 12

Multi-targeted tyrosine kinase inhibitor
Blocks tumour growth + inhibits angiogenesis
Inhibits VEGFR
Acts as ATP-mimic

Question 13

Describe Pazopanib properties

Answer 13

Renal cell carcinoma
CYP metabolism = administered with CYP inhibitors
SE = N+V, diarrhoea, changes in hair colour, HTN rash + fatigue