BCH3042 Lecture Notes - Lecture 20: Small-Cell Carcinoma, Protein Kinase Inhibitor, Receptor Tyrosine Kinase
25 May 2018
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Lecture 20 – Small Molecule Drugs Targeting Protein Kinases (Erlotinib,
Gefitinib, Crizotinib)
Active site of protein Kinases is a Major Target for Drug Development
• ATP-binding pocket lies within a cleft bordered by the N and C lobes and
connecting hinge
o Where enzymatic reaction occurs
o 3 phosphates of ATP faces solvent
• ATP binding involves H-bonds between ATP and hinge region
• Y-phosphate is poised for transfer to hydroxyl group of a tyrosine residue
• Can develop small molecular drugs that inhibit this process
Protein Kinases can be Inhibited by Small Molecule Drugs
• Two types of kinase inhibitor bind in ATP pocket
o Type I: bind to active conformation of a
kinase and are ATP-competitive
▪ DFG in, active conformation
o Type II: bind to inactive conformation
▪ Lock kinase in inactive state
▪ DFG out, kinase inactive
conformation
• Type III inhibitors bind outside of ATP binding
pocket and are non-ATP competitive
o Don’t interfere with ATP binding
o Harder to develop
▪ Offer greater selectivity
Targeting non small cell lung cancer with EGFR and ALK Tyrosine Kinase Inhibitors
(TKIs)
ErbB1 (HER1, EGFR) as Therapeutic Target
• EGFR structure and signalling
o EGFR binding promotes receptor
dimerization, kinase activation and stimulation
of downstream signalling pathways (e.g.
Ras/Erk, P13K/Akt)
• Tumours with High EGFR expression
o Head and neck (60-90%)
o Prostate (40-80%)
o Gastric → breast → colorectal
Non Small Cell Lung Cancer (NSCLC)
• 80% of lung cancers
• NSCLC Disease stage dictates treatment
o 0-II (localised disease): surgery
o III, IV (invasive, metastatic): radiation, chemo, targeted therapy
• 85% NSCLC diagnosed at stage III-IV: advanced or metastatic disease with
poor prognosis
o Stage 0-IIIB: 5 year survival
o Stage IV: 5 year survival
• Therapies for treatment of NSCLC
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