Discovery of novel Bcr-AblT315I inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-Abl^WT and Bcr-Abl^T315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-Abl^WT and Bcr-Abl^T315I kinases with IC₅₀ of 0.043 μM and 0.17 μM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC₅₀ of 1.65 μM and 5.42 μM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.

CML; Hinge binding moiety; Phenyl-1H-indazol-3-amine; T315I; mutantFlexible linker.