title: Discovery of new benzothiazole-based inhibitors of breakpoint cluster region-Abelson kinase including the T315I mutant.
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.
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Hong
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.forename: Yoonsu
authors.initials: Y
authors.lastname: Park
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D015739:Nocodazole / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; C005465:benzothiazole; D015739:Nocodazole