Lapatinib

ERBB2, EGFR

581, 06

CD-1 nude female mice implanted s.c. with HN5 cells, and C.B-17 SCID female mice implanted s.c. with BT474 cells

A Phase II study of Lapatinib in treating patients with recurrent prostate cancer has been completed.

ca.100 mg/kg

10.8 nM, 10.8 nM, 10.8 nM, 10.8 nM, 10.8 nM, 10.8 nM

Oral administration of Lapatinib (ca.100 mg/kg) twice daily significantly inhibits the growth of BT474 and HN5 xenografts in a dose-dependent manner. [1]

In vitro kinase assays, The IC50 values for inhibition of enzyme activity are generated by measuring inhibition of phosphorylation of a peptide substrate. The intracellular kinase domains of EGFR and ErbB2 are purified from a baculovirus expression system. EGFR and ErbB2 reactions are performed in 96-well polystyrene round-bottomed plates in a final volume of 45 uL. Reaction mixtures contain 50 mM 4-morpholinepropanesulfonic acid (pH 7.5), 2 mM MnCl2, 10 uM ATP, 1 uCi of [gamma33P] ATP/reaction, 50 uM Peptide A [Biotin-(amino hexonoic acid)-EEEEYFELVAKKK-CONH2], 1 mM dithiothreitol, and 1 uL of DMSO containing serial dilutions of Lapatinib beginning at 10 uM. The reaction is initiated by adding the indicated purified type-1 receptor intracellular domain. The amount of enzyme added is 1 pmol/reaction (20 nM). Reactions are terminated after 10 minutes at 23C by adding 45 uL of 0.5% phosphoric acid in water. The terminated reaction mix (75 uL) is transferred to phosphocellulose filter plates. The plates are filtered and washed three times with 200 uL of 0.5% phosphoric acid. Scintillation cocktail (50 uL) is added to each well, and the assay is quantified by counting in a Packard Topcount. IC50 values are generated from 10-point dose-response curves.

DMSO 116 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL

N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine, di4-methylbenzenesulfonate