Dasatinib is an Orally Active Dual Bcr-Abl and Src Family Tyrosine Kinase Inhibitor

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.

Dasatinib is an Orally Active Dual Bcr Abl and Src Family Tyrosine Kinase Inhibitor 2021 04 17 - Dasatinib is an Orally Active Dual Bcr-Abl and Src Family Tyrosine Kinase Inhibitor

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.