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Research Article

Screening and Activity Evaluation of Novel BCR-ABL/T315I Tyrosine Kinase Inhibitors


Jie Su, Chenggong Fu, Shuo Wang, Xuelian Chen, Runan Wang, Huaihuai Shi, Jiazhong Li* and Xin Wang   Pages 1 - 23 ( 23 )


Introduction: Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti- CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a "gatekeeper" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical.

Methods: This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and western blot experiments.

Results: The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound No 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins.

Conclusion: The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.


Chronic myeloid leukemia,BCR-ABL,Tyrosine kinase,T315I,Inhibitor,Virtual screening,compound


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