Discovery of new benzothiazole-based inhibitors of breakpoint cluster region-abelson kinase including the T315i mutant

Seunghee Hong, Jinhee Kim, Sun Mi Yun, Hyunseung Lee, Yoonsu Park, Soon Sun Hong, Sungwoo Hong

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3531-3545
Number of pages15
JournalJournal of Medicinal Chemistry
Volume56
Issue number9
DOIs
StatePublished - 9 May 2013
Externally publishedYes

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