Oncologia medica - iInibitori delle TK

Inibitori delle TK

Small molecule HER-tyrosine kinase (TK) inhibitors

• Rationale: Prevent HER activation and inhibit the tumorigenic effects associated with HER overexpression.
• Mechanism of action: Inhibit TK phosphorylation by competing with ATP for binding with the intracellular catalytic domain of TK.
• Agents:
  • HER1-TK inhibitors
  • Dual HER1/2-TK inhibitors
  • Pan HER-TK inhibitors

TM Tarceva, PKI-166, CI-1033 TM Iressa, GW2016, PD158780, EKB-569

Mechanism of action and effects

Ligand HER1 extracellular ligand-binding domain. Cell membrane HER1 cytoplasmic TK domain.

Inhibition: TK domain leading to chemotherapy sensitivity, reduced adhesion, decreased angiogenesis, survival, proliferation, and invasion.

Clinical potential

• Good tolerability
• Use in multiple tumor types
• Use in early- and late-stage disease
• Use as monotherapy or in combination with standard therapies

TM Tarceva: Structure and properties

• Quinazoline
• Orally available
• Selective inhibitor of HER1 TK:
  • Purified HER1 kinase IC₅₀ = 2nM
  • Purified HER2 kinase IC₅₀ = 350nM
  • Cell-based assay IC₅₀ = 20nM
• Reversible inhibitor
• Inhibits HER1 phosphorylation in head and neck xenografts with an erlotinib (OSI-774) ED₅₀ of 10mg/kg/day
• Delays tumor growth and induces regression in xenograft models
• Enhances the activity of various cytotoxic agents

TM Tarceva: Selective inhibition of HER1 phosphorylation

Target (nM IC₅₀):

• HER1: 2
• HER2: 100
• VEGFR: 600
• IGF-1R: >10,000
• CSF-1R: >10,000
• met: 1,300
• src: 1,500
• abl: >10,000
• lck: >10,000

Concentration of Tarceva (µM): 0.0001, 0.001, 0.01, 0.1, 1, 10

Adapted from Moyer J, et al. Cancer Res 1997; 57:4838–48

TM Antitumour effect of Tarceva

HN5 carcinoma xenograft growth in athymic mice

Treatment groups:

• Vehicle control
• 1.6 mg/kg/day p.o.
• 12.5 mg/kg/day p.o.
• 50.0 mg/kg/day p.o.
• 100 mg/kg/day p.o.

Tumor volume (mm³) over time after implantation (days): 0, 10, 20, 30, 40, 50, 60, 70

Pollack V, et al. J Pharm