生物活性

• 描述Many of the processes involved in tumor growth, progression, and metastasis are mediated by ligand-receptor interactions involving RTKs (receptor tyrosine kinases) and downstream signaling molecules. Because of the demonstrated importance of RTKs in the control of many cellular processes (particularly proliferation) and the role of aberrant RTK signaling in cancer, RTKs have emerged as important targets for the development of anticancer therapies. Toceranib, a small molecule with an indolinone chemical structure, is a selective inhibitor of the tyrosine kinase activity of several members of the split kinase RTK family, including Flk-1/KDR, PDGFR, and Kit. In vitro, toceranib exerted a potent antiproliferative effect on endothelial cells. Additionally, toceranib treatment could induce cell cycle arrest and subsequent apoptosis in tumor cell lines expressing activating mutations in split kinase RTKs. In mouse xenograft models, oral administration of toceranib affected the growth of multiple tumor cell lines originating from a variety of tissues, leading to either tumor regression or tumor growth inhibition. On the basis of preclinical work in rodent models, the therapeutic range of toceranib for target inhibition was considered to be 50–100 ng/ml for 12 h of a 24-h dosing period^[3].
• 作用机制Toceranib competes directly with ATP at the intracellular kinase domain of the RTK, thus preventing tyrosine phosphorylation and subsequent signal transduction^[3].