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Theexistence of drug resistance caused by mutations in the break-pointcluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remainsa clinical challenge due to limited effective treatment options forchronic myeloid leukemia (CML). Herein we report a novel series ofbenzothiazole-based inhibitors that are effective against wild-typeand 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 thescaffold. In addition, the introduction of water-solubilizing groupsat the terminal ethyl group resulted in enhanced physicochemical propertiesand potency in cellular inhibition. Several compounds inhibited thekinase activity of both wild-type Bcr-Abl and the T315I mutant withIC50values in the picomolar range and exhibited good antiproliferativeeffects on Ba/F3 cell lines transformed with either wild-type or T315Imutant Bcr-Abl. [ABSTRACT FROM AUTHOR]

Tropomyosin-related kinase A (TrkA) is considered a promisingtarget in the development of a therapeutic treatment of cancer andpain. In this study, we designed and synthesized a series of novel7-azaindole-based Trk kinase inhibitors through the structure-baseddesign strategy. By varying the functional groups at the 3 and 5 positionsof a 7-azaindole scaffold, we studied the structure–activityrelationships (SAR) profiles and identified a series of potent Trkinhibitors. Representative derivatives showed desirable activity incellular proliferation and apoptosis assays. Moreover, these inhibitorsexhibited noteworthy antiangiogenic activity. [ABSTRACT FROM AUTHOR]