SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia

• Published in: European journal of pharmacology Vol. 811; pp. 117 - 124
• Main Authors: Wang, Duowei, Zheng, Yan, Li, Jiaying, Wu, Hongxi, Li, Xianjing, Tang, Ying, Liu, Yang, Li, Jiani, Sun, Rui, Zhou, Youli, Sun, Jihong, Yang, Yong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2017
• Subjects: Animals; BCR-ABL; Cell Line, Tumor; Cell Proliferation - drug effects; Chronic myeloid leukemia (CML); Drug Resistance, Neoplasm - drug effects; Female; Fusion Proteins, bcr-abl - genetics; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Mice; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; SHC004-221A1; Signal Transduction - drug effects; T315I mutation; Xenograft Model Antitumor Assays; Ponatinib (PubChem CID: 24826799); T315I mutation; Dasatinib (PubChem CID: 3062316); Imatinib mesylate (PubChem CID: 123596); BCR-ABL; Chronic myeloid leukemia (CML); Nilotinib (PubChem CID: 644241); SHC004-221A1
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2017.06.001

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.