1. SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia
- Author
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Jiani Li, Jihong Sun, Hongxi Wu, Jiaying Li, Yan Zheng, Rui Sun, Liu Yang, Xianjing Li, Yong Yang, Duowei Wang, Ying Tang, and Youli Zhou
- Subjects
Male ,0301 basic medicine ,Mutant ,Fusion Proteins, bcr-abl ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,Pharmacology ,Chemistry ,Myeloid leukemia ,Protein-Tyrosine Kinases ,Xenograft Model Antitumor Assays ,Fluorobenzenes ,CRKL ,030104 developmental biology ,Protein kinase domain ,Drug Resistance, Neoplasm ,Purines ,030220 oncology & carcinogenesis ,Cancer research ,Phosphorylation ,Female ,Signal transduction ,Tyrosine kinase ,Signal Transduction - Abstract
Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABLT315I. In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL. Signaling pathway analysis revealed that SHC004-221A1 inhibited the phosphorylation of STAT5 and CrkL, which contributed to the apoptosis of CML cells. In vivo studies indicated that SHC004-221A1 suppressed BCR-ALBT315I-driven tumor growth in mice. Taken together, the results of this study suggested that SHC004-221A1 may be a promising BCR-ABLT315I inhibitor for the treatment of CML.
- Published
- 2017
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