dasatinib and benzothiazole

Three series of novel 4-benzothiazole amino quinazolines Dasatinib derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro cytotoxic activity by the MTT-based assay against 6 human cancer cell lines. Compared with the parental Dasatinib, most of the new compounds, especially 2, 4, 6-trimethylaniline series (3), demonstrated significant inhibitory activities against six cell lines. Furthermore, the target compounds were screened for Src and Abl kinase inhibitory activity. Among them, 1a, 1f and 3a-3f are more potential dual Src/Abl kinase inhibitors. Thus they may be promising lead compounds to be developed as an alternative for current Dasatinib therapy or for Imatinib-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.

Topics: Antineoplastic Agents; Benzothiazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dasatinib; Dose-Response Relationship, Drug; Drug Design; HCT116 Cells; Humans; Inhibitory Concentration 50; K562 Cells; Models, Chemical; Molecular Structure; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; Quinazolines; src-Family Kinases; Thiazoles; U937 Cells

The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

Topics: Animals; Benzothiazoles; Cell Line; Cell Proliferation; Drug Design; Fusion Proteins, bcr-abl; Mice; Molecular Docking Simulation; Mutation; Nocodazole; Protein Kinase Inhibitors; Protein Structure, Tertiary; Signal Transduction