SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia
SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia
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SHC004-221A1 是一种新型酪氨酸激酶，可有效抑制慢性粒细胞白血病中的 T315I 突变体 BCR-ABL
DOI：
10.1016/j.ejphar.2017.06.001
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发表时间：
2017
影响因子：
5
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Wang Duowei;Zheng Yan;Li Jiaying;Wu Hongxi;Li Xianjing;Li Jiani;Sun Rui;Zhou Youli;Sun Jihong;Yang Yong;Tang Ying;Liu Yang;Sun Jihong;Sun JH;Yang Y
尽管明智地使用靶向BCR-ABL的酪氨酸激酶抑制剂是控制慢性髓性白血病（CML）的有效策略，但由于激酶结构域突变，其中主要是BCR-ABLT315I，因此观察到耐药。在这项研究中，我们发现SHC004-221A1是T315I和其他BCR-ABL突变体的有效抑制剂。生化实验表明，SHC004-221A1对所有选定的BCR-ABL突变体均有抑制作用。体外研究表明，SHC004-221A1抑制了携带原生和T315I突变体BCR-ABL的肿瘤细胞系的增殖。信号通路分析显示SHC004-221A1抑制STAT5和CrkL的磷酸化，参与CML细胞的凋亡。体内研究表明，SHC004-221A1抑制bcr - albt315i驱动的小鼠肿瘤生长。综上所述，本研究结果提示SHC004-221A1可能是一种治疗CML的有前景的bcr - ablt315i抑制剂。
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-ABLT315Iinhibitor for the treatment of CML.