Design, synthesis and structure-activity relationship of a series of novel BCR-ABL inhibitors

In this study, molecular skeleton I N-phenylindoline-5-formamide was obtained by optimizing the structure of the existing allosteric BCR-ABL inhibitor asciminib. Based on this molecular skeleton, compounds 1-12 were designed and synthesized assisted by molecular docking. After characterizing their structures using ESI-MS and NMR, the anti-BCR-ABL1-dependent Luc-Ba/F3 cell proliferation activity of the target compounds in vitro was determined by CCK-8 assay. Finally, highly active lead compound 1 was screened out. For high clearance rate and short half-life period exposed in subsequent druggability evaluation, its druggability was optimized by introducing hydrophilic groups. Afterwards, compounds 13-22 were designed and synthesized. Compound 17 presented high cell inhibitory activity, low clearance rate and long half-life, and is expected to be used as a clinical candidate for further evaluation of biological activity and druggability.