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HS-438, a new inhibitor of Imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

Authors
  • Yun, Sun-Mi
  • Jung, Kyung Hee
  • Kim, Soo Jung
  • Fang, Zheng Huan
  • Son, Mi Kwon
  • Yan, Hong Hua
  • Lee, Hyunseung
  • Kim, JinHee
  • Shin, Sanghye
  • Hong, Sungwoo
  • Hong, Soon-Sun1, 2, 3, 4, 5, 6, 7, 8
  • 1 College of Medicine
  • 2 Inha University
  • 3 3-ga
  • 4 Sinheung-dong
  • 5 Colleges of Pharmacy
  • 6 Chonnam National University
  • 7 Department of Chemistry
  • 8 Korea Advanced Institute of Science and Technology (KAIST)
Type
Published Article
Journal
Cancer Letters
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Mar 07, 2014
Identifiers
DOI: 10.1016/j.canlet.2014.03.012
Source
Elsevier
Keywords
License
Unknown

Abstract

Imatinib is a selective breakpoint cluster region–Abelson (BCR-ABL) tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, T315I gene mutations of the BCR-ABL kinase domain have been shown to confer resistance to Imatinib. In the present study, we synthesized a novel BCR-ABL inhibitor, HS-438, and identified its anti-leukemic effects in vitro and in vivo. We found that HS-438 strongly inhibited the expression of BCR-ABL signaling pathways in wild-type BCR-ABL (BaF3/WT) cells as well as T315I-mutated BCR-ABL (BaF3/T315I) cells with resistance to Imatinib. HS-438 induced cell cycle arrest, particularly during the G0/G1 cell cycle phase, and induced apoptosis. In BaF3/T315I xenograft models, HS-438 significantly delayed tumor growth, unlike Imatinib. In summary, we suggest that HS-438 may be a novel drug candidate with the therapeutic potential to target BCR-ABL and overcome Imatinib resistance in patients with CML.

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