Description
Desmethyl Erlotinib (CP-473420, OSI-774) is a free base of OSI-420, the active metabolite of Erlotinib (EGFR inhibitor with IC50 of 2 nM).
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Molecular Formula
C21H21N3O4
Chemical Name
2-(4-(3-ethynylphenylamino)-7-(2-methoxyethoxy)quinazolin-6-yloxy)ethanol
Solubility
DMSO 11 mg/mL; Water <1 mg/mL; Ethanol 5 mg/mL
In vitro
OSI-420 is the major metabolite of Erlotinib in human plasma. Erlotinib disappearance from plasma after a short IV infusion is biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma is 30% (range 12-59%) of erlotinib, and OSI-420 clearance is more than 5-fold higher than erlotinib. Erlotinib and OSI-420 are equipotent, and the combined concentrations of erlotinib + OSI-420 achieved in the CSF exceeded the IC50 (7.9 ng/ml or 20 nM) for the EGFR tyrosine kinase inhibition in intact tumor cells. Erlotinib potently inhibits EGFR activation in intact cells including HNS human head and neck tumor cells (IC50 20nM), DiFi humancolon cancer cells andMDA MB-468 human breast cancer cells. Erlotinib (1 μM) induces apoptosis in DiFi humancolon cancer cells.Erlotinib growth of a panel of NSCLC cell lines including A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596 with IC50 ranging from 29 nM to >20 μM.Erlotinib(2 μM) significantly inhibits growth of AsPC-1 and BxPC-3 pancreatic cells.The effects of Erlotinib HCl in combination with gemcitabine are considered additive in KRAS-mutated pancreatic cancer cells. Ten micromolar of Erlotinib inhibits EGFR phospho-rylation at the Y845 (Src-dependent phosphorylation) and Y1068 (auto-phosphorylation) sites.Combination with Erlotinib could down-modulate rapamycin-stimulated Akt activity and produces a synergistic effect on cell growth inhibition.
In vivo
At doses of 100 mg/kg, Erlotinib HCl completely prevents EGF-induced autophosphorylation of EGFR in human HN5 tumors growing as xenografts in athymic mice and of the hepatic EGFR of the treated mice.Erlotinib HCl (100 mg/Kg) inhibits H460a and A549 tumor models with 71 and 93% inhibition rate.
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