Src is an important member of the non-receptor protein tyrosine kinase. Furthermore, Src plays a key role in the regulation of many cells through the extracellular ligand binding to the receptor and the cell adhesion molecule activation in cell cycle-specific stage. Src can affect cell adhesion, motility, proliferation, and angiogenesis. BCR-ABL1 oncoprotein is the molecular hallmark of chronic myelogenous leukemia displaying constitutive tyrosine kinase activity. The effects induce the activation of several intracellular pathways such as PI3K/AKT/mTOR, RAS/ERK, and JAK/STATs. Dasatinib acts as a potent Src/Abl kinase inhibitor with excellent antiproliferative activity against hematological and solid tumor cell lines.
Src-family kinases have an important role in many oncologic functions in human cancers, including proliferation, motility, migration, survival, and angiogenesis. Src tyrosine kinase inhibitors have shown a favorable safety profile and moderate anticancer activity in unselected patient populations. Dasatinib is orally active in a K562 xenograft model of chronic myelogenous leukemia, demonstrating complete tumor regressions and low toxicity at multiple dose levels.
Dasatinib is a highly potent, ATP competitive inhibitor of both Src and Bcr-Abl, with Kis of 16 pM and 30 pM, respectively. Moreover, Dasatinib potently inhibits other Src-family members. Dasatinib also demonstrates significant activity against c-kit and PDGFRβ. Following once-daily doses of either 5 or 50 mg/kg, Dasatinib shows partial tumor regressions after one treatment cycle and complete disappearance of the tumor mass. As a result, Dasatinib possesses potent in vivo activity and a high safety margin in this animal model of chronic myelogenous leukemia.
In summary, Dasatinib is a tyrosine kinase inhibitor. Dasatinib blocks BCR-ABL and other proteins, which may help keep cancer cells from growing.
Louis J Lombardo, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004 Dec 30;47(27):6658-61.