Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase.
The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.
Ellis
A G
AG
Pharmacology and Developmental Therapeutics Unit, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
Doherty
M M
MM
Walker
F
F
Weinstock
J
J
Nerrie
M
M
Vitali
A
A
Murphy
R
R
Johns
T G
TG
Scott
A M
AM
Levitzki
A
A
McLachlan
G
G
Webster
L K
LK
Burgess
A W
AW
Nice
E C
EC
D000818:Animals; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D015394:Molecular Structure; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011799:Quinazolines; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D020032:Tyrphostins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases; D013936:Thymidine