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

Duowei Wang; Yan Zheng; Jiaying Li; Hongxi Wu; Xianjing Li; Ying Tang; Yang Liu; Jiani Li; Rui Sun; Youli Zhou; Jihong Sun; Yong Yang

doi:10.1016/j.ejphar.2017.06.001

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

Eur J Pharmacol. 2017 Sep 15:811:117-124. doi: 10.1016/j.ejphar.2017.06.001. Epub 2017 Jun 6.

Authors

Duowei Wang¹, Yan Zheng¹, Jiaying Li¹, Hongxi Wu¹, Xianjing Li¹, Ying Tang², Yang Liu², Jiani Li¹, Rui Sun¹, Youli Zhou¹, Jihong Sun³, Yong Yang⁴

Affiliations

¹ State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
² Pharmacology Department, Nanjing SANHOME Pharmaceutical CO., LTD., R&D Center, Nanjing, China.
³ State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China; Pharmacology Department, Nanjing SANHOME Pharmaceutical CO., LTD., R&D Center, Nanjing, China. Electronic address: [email protected].
⁴ State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].

PMID: 28595903
DOI: 10.1016/j.ejphar.2017.06.001

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-ABL^T315I. 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-ALB^T315I-driven tumor growth in mice. Taken together, the results of this study suggested that SHC004-221A1 may be a promising BCR-ABL^T315I inhibitor for the treatment of CML.

Keywords: BCR-ABL; Chronic myeloid leukemia (CML); Dasatinib (PubChem CID: 3062316); Imatinib mesylate (PubChem CID: 123596); Nilotinib (PubChem CID: 644241); Ponatinib (PubChem CID: 24826799); SHC004-221A1; T315I mutation.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Female
Fluorobenzenes / pharmacology*
Fluorobenzenes / therapeutic use
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*
Purines / pharmacology*
Purines / therapeutic use
Signal Transduction / drug effects
Xenograft Model Antitumor Assays

Substances

Fluorobenzenes
Protein Kinase Inhibitors
Purines
SHC004-221A1
Protein-Tyrosine Kinases
Fusion Proteins, bcr-abl