2. Academic Validation
  3. HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia

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

  • Cancer Lett. 2014 Jun 28;348(1-2):50-60. doi: 10.1016/j.canlet.2014.03.012.
Sun-Mi Yun 1,  Kyung Hee Jung 2,  Soo Jung Kim 1,  Zhenghuan Fang 1,  Mi Kwon Son 1,  Hong Hua Yan 1,  Hyunseung Lee 1,  JinHee Kim 3,  Sanghye Shin 3,  Sungwoo Hong 4,  Soon-Sun Hong 5
Affiliations

Affiliations

  • 1 College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
  • 2 College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea; College of Pharmacy, Chonnam National University, Gwang-Ju 300, Republic of Korea.
  • 3 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
  • 4 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: hongorg@kaist.ac.kr.
  • 5 College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address: hongs@inha.ac.kr.
PMID: 24657654 DOI: 10.1016/j.canlet.2014.03.012
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.

Keywords

BCR-ABL; Chronic myeloid leukemia; HS-438; T315I.

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