A quinazoline and butenamide derivative that acts as a tyrosine kinase inhibitor of epidermal growth factor receptors (ERBB RECEPTORS) and is used in the treatment of metastatic NON-SMALL CELL LUNG CANCER.
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling and blocking EGFR-dependent proliferation.
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alfa/beta, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family. Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.
Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-beta). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma.
An indole and pyrrole derivative that inhibits VEGFR-2 and PDGFR BETA RECEPTOR TYROSINE KINASES. It is used as an antineoplastic agent for the treatment of GASTROINTESTINAL STROMAL TUMORS, and for treatment of advanced or metastatic RENAL CELL CARCINOMA.
In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR. In vitro, vandetanib inhibited epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells. In vivo, vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.