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Binding of insulin to its binding site (one on each of theachains) causes a

conformational change that activates the kinase activity. In the case of EGFRs, agonist

binding causes either a conformational change that allows the occupied receptors to

recognise each other resulting in their association to form homo- or heterodimers

or stabilises a pre-existing equilibrium between monomers and dimers and induces

conformational changes within the dimer. At this stage the kinase action of

the receptor is inactive, but the dimerisation is rapidly followed by the mutual

cross-autophosphorylation of one to three Tyr residues in the tyrosine kinase domains

Example 3 (cont.)

Drug Target Mechanism

Gefitinib

(Iressa) – a small

molecule

Binds to the ATP binding site

of the tyrosine kinase

domain of epidermal growth

factor receptor (EGFR) in

non-small-cell lung cancer

Inhibits the activation of the

Ras signal transduction

cascade thereby inhibiting

tumour growth

Trastuzumab

(Herceptin) – an

antibody

HER2 receptor, a member of

the EGFR family

Blocks HER2 receptor

preventing it from forming

dimers with similar receptors

that cause a signal to the

nucleus to stimulate the

tumour to grow and divide

Tositumomab

(Bexxar) – an

antibody

carrying^131 I

CD20 receptor onb-cells Binds to receptor and the

radioactive iodine isotope

that it carries kills cancerous

lymphoma cells

Rituximab

(MabThera) – a

chimeric

monoclonal

antibody

CD20 receptor onb-cells Triggers the immune system

to destroy healthy and

lymphoma cells

Tamoxifen

(Nolvadex) – a

small molecule

Oestrogen receptor Decreases DNA synthesis and

inhibits oestrogen effects that

cause the tumour to grow

Sorafenib

(Nexavar) – a

small prodrug

molecule

Vascular endothelial growth

factor receptor (VEGFR) and

platlet-derived growth factor

receptor (PDGFR) on cells

lining blood vessels

Inhibits protein kinase

activity of receptors. Also

binds to c-kit receptors on

cancer cell involved in cancer

growth

Like the treatment for HIV/AIDS (Section 18.2.2) cancer therapy most commonly

involves the use of a cocktail of drugs acting by different mechanisms.

700 Cell membrane receptors and cell signalling