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

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.

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