Oncologia medica - iInibitori delle TK

Inibitori delle TK

Small molecule HER-tyrosine

kinase (TK) inhibitors

• –

Rationale prevent HER activation and inhibit the

tumourigenic 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 Dual HER1/2-TK Pan HER-TK

inhibitors inhibitors inhibitors

TM

Tarceva PKI-166 CI-1033

TM

Iressa GW2016 PD158780

EKB-569

Mechanism of action and effects

Ligand

HER1 extracellular

ligand-binding R R

domain Cell membrane

HER1

cytoplasmic K K

TK domain P P

Mechanism of action and effects

Ligand

HER1 extracellular

ligand-binding R R

domain Cell membrane

HER1 



cytoplasmic K K Inhibition

TK domain  Chemotherapy

 Adhesion sensitivity

 

Angiogenesis Survival

 

Proliferation Invasion

Clinical potential

• Good tolerability

• Use in multiple tumour 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 IC =2nM

50

– purified HER2 kinase IC =350nM

HN 50

– cell-based assay IC =20nM

50

O

O N • Reversible inhibitor

O N

O .HCl • Inhibits HER1 phosphorylation in

head and neck xenografts with an

erlotinib (OSI-774) ED of 10mg/kg/day

50

• Delays tumour growth and induces

regression in xenograft models

• Enhances the activity of various

cytotoxic agents

TM

Tarceva : selective inhibition

of HER1 phosphorylation

120 (nM)

IC

Target 50 2

HER1

control) 100 350

HER2 600

VEGFR

80

(% >10,000

IR

HER1

Phosphorylation 60 >10,000

IGF-1R

IGF-1R >10,000

CSF-1R

40 IR >10,000

met

20 1,300

src 1,500

abl

0 >10,000

lck

0.0001 0.001 0.01 0.1 1 10

™

Concentration of Tarceva (µM)

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

TM

Antitumour effect of Tarceva

HN5 carcinoma xenograft growth in athymic mice

2,500 Vehicle control

1.6mg/kg/day p.o.

2,000 12.5mg/kg/day p.o.

)

3

(mm 50.0mg/kg/day p.o.

100mg/kg/day p.o.

1,500

volume 1,000 Treatment period

Tumour 500

0 0 10 20 30 40 50 60 70

Time after implantation (days)

Pollack V, et al. J Pharmacol Exp Ther 1999;291:739–48

TM

Iressa : structure and

properties

• Quinazoline

• Orally available

• Selective inhibitor of HER1 TK

F – HER1 IC =23nM

50

– HER2 IC =120–370nM

CI 50

O HN • Reversible inhibitor

N O N • Inhibits ligand-induced cell

H C

3 O N growth; IC =0.08µM

50

• Delays tumour growth and

ZD1839 induces regression in

xenograft models

• Enhances the activity of

various cytotoxic agents

and radiotherapy

Growth inhibition of human

TM

tumour xenografts by Iressa

GEO (colon)

100 OVCAR-3 (ovarian)

growth control ZR-75-1 (breast)

80 MCF-10A Ha-ras (breast)

cell 60

with

Percentage compared 40

20

0 0.01 0.1 1 10

TM

Concentration of Iressa (µM)

Values are mean (SD) Ciardiello F, et al. Clin Cancer Res 2000;6:2053–63

TM

Antitumour activity of Iressa and

paclitaxel against human tumour xenografts

Control Paclitaxel

TM TM

Iressa Iressa + paclitaxel

1,200 1,200

LX-1 lung PC-3 prostate

1,000 1,000

(mg) (mg)

800 800

mass mass

600 600

Tumour Tumour

400 400

200 200

0 0

0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36

Time (days) Time (days)

Sirotnak F, et al. Clin Cancer Res 2000;6:4885–92

HER1 inhibitors block receptor

signalling in patients (MAP kinase)

Pre-Iressa Post-Iressa

TM TM