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J Med Chem. 2013 May 9;56(9):3531-45. doi: 10.1021/jm301891t. Epub 2013 Apr 19.

Discovery of new benzothiazole-based inhibitors of breakpoint cluster region-Abelson kinase including the T315I mutant.

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Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.


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.

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