Molecular Mechanisms of Resistance to Imatinib (STI571, CGP57148B)

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Molecular Mechanisms of Resistance to Imatinib
(STI571, CGP57148B)
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Structure of Imatinib (STI571, CGP 57148B)
O
CH3SO3H

• Class Phenylaminopyrimidines, 589.7 mw

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Cellular Selectivity of STI571 IC50µM

• Kinases Inhibited Kinases Not Inhibited
• v-ABL 0.10.3 Flt-3 gt10
• p210bcr-abl 0.25 c-Fms, v-Fms gt10
• p185bcr-abl 0.25 EGF receptor gt100
• TEL-Abl 0.35 c-erbB2 gt100
• PDGF receptor 0.1 Insulin receptor gt100
• TEL-PDGF IGF-1 receptor gt100
• receptor 0.15 v-Src gt10
• c-kit 0.1 JAK-2 gt100

Druker BJ et al. Nat Med. 19962561-566
Personal communication 4/00. B Druker, E
Buchdunger.
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Effect of STI571 on Growth ofBcr-AblPositive
and Negative Cell Lines
120
100
80
Control CPM
60
U937 KG1 KCL22 K562 KU812 SU DHL1
40
20
0
0
0.1
0.3
1
3
10
Bcr-Abl-negative cell lines Bcr-Abl-positive
cell lines
STI571 Concentration (mM)
Gambacorti-Passerini C et al. Blood Cells Mol
Dis. 199723380.
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LAMA84 Control
LAMA84 24h 1uM
LAMA84 44h 1 uM
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Resistance to Imatinib
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IDiscontinuous Inhibition
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i.p. 2h p.o. i.p. 5h p.o.
i.p. 9h p.o.
bcr/abl
anti-phosphotyrosine
bcr/abl
anti-abl
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IIInsufficient Tissue Levels(Beware of Plasma
Concentrations)
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alpha 1 acidic glycoprotein
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Patient 001
Anti-Abl
205 kd
205 kd
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Effect of the administration of Clindamycin (900
mg i.v. over 20 minutes) on STI571 plasma
concentrations
8
g/ml)
7
6
m
5
4
3
Patient 008
2
Patient 00213
0.4
Patient 00241
STI571 Plasma concentration (
0.3
Clindamycin
0.2
0.1
0.0
0
10
20
30
Time (min)
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Effect of Clindamycin (C) administration on
steady state STI571 plasma levels
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In the presence of alpha 1 acidic glycoprotein
(AGP)
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Trattamento con STI571 Eritromicina (E)
BCR/ABL
STI 571
STI 571
STI 571
STI 571
AGP
AGP
AGP
AGP