lapatinib brands

Molecular formula: C29H26ClFN4O4S

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of &ge;300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. Lapatinib (GW572016) is a small-molecule dual inhibitor of epidermal growth factor receptor (ErbB1) and ErbB2 receptor kinase activities currently in phase III clinical trials. ... Phosphoprotein and microarray analyses /were used/ to carry out targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib. Studies were done in four breast cancer cell lines, two of which were responsive and two of which were nonresponsive to lapatinib. Responsive cell lines, BT474 and SKBr3, constitutively overexpress ErbB2 and show an IC(50) of 25 or 32 nmol/L for lapatinib, respectively. In contrast, nonresponsive MDA-MB-468 and T47D cells expressed a low basal level of ErbB2 and showed IC(50) values in the micromolar range. Cells responsive to lapatinib exhibited strong differential effects on multiple genes in the AKT pathway. After 12 hr of exposure to 1.0 umol/L of lapatinib, AKT1, MAPK9, HSPCA, IRAK1, and CCND1 transcripts were down-regulated 7- to 25-fold in responsive BT474 and SKBr3 cells. In contrast, lapatinib weakly down-regulated the AKT pathway in nonresponsive breast cancer cell lines (<5-fold down-regulation of most genes in the pathway). Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib-responsive SKBr3 and BT474 cells, respectively. Phosphorylated Akt and Akt-mediated phosphorylation of FOXO3A also decreased in responsive breast cancer cell lines exposed to lapatinib. Gene expression profiling also revealed that lapatinib stimulated the expression of estrogen and progesterone receptors and modulated the expression of genes involved in cell cycle control, glycolysis, and fatty acid metabolism. In BT474 and T47D cells, which expressed moderate basal levels of the estrogen and progesterone receptors, 1.0 micromol/L of lapatinib induced expression by 7- to 11-fold. These data provide insight into the mechanism of action of lapatinib in breast cancer cells. Lapatinib is a tyrosine kinase inhibitor which dually inhibits the growth factor receptors ErbB1 (epidermal growth factor receptor, EGFR) and ErbB2 (HER2). Lapatinib is a member of the 4-anilinoquinazoline class of kinase inhibitors. Members of this class of molecules have been shown to bind to the ATP binding site of protein kinases and compete with the ATP substrate. This blocks receptor phosphorylation and activation, preventing subsequent downstream signalling events. ErbB2 is one of four members of a family of genes encoding transmembrane receptors for growth factors, the other three being ErbB1 (EGFR or HER1), ErbB3 (HER3) and ErbB4 (HER4). There is evidence ... that induced overexpression of ErbB1 or ErbB2 receptors in cells in vitro produces phenotypes associated with oncogenic transformation, such as the ability to grow in soft agar and formation of tumors in nude mice. In vivo, overexpression of ErbB1 or ErbB2 has been reported in a variety of human tumors and has been associated with poor prognosis and reduced overall survival in patients with cancer. Several

Source: PubChem (NCBI) · compound 208908