Research Papers:

HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation

Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Mi Kwon Son, Zhenghuan Fang, Ye-Lim Ryu, Hyunseung Lee, Joo Han Lim, Jun-Kyu Suh, JinHee Kim, Soyoung Lee, Sungwoo Hong and Soon-Sun Hong _

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Oncotarget. 2015; 6:1507-1518. https://doi.org/10.18632/oncotarget.2837

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Soo Jung Kim1,*, Kyung Hee Jung1,*, Hong Hua Yan1, Mi Kwon Son1, Zhenghuan Fang1, Ye-Lim Ryu1, Hyunseung Lee1, Joo Han Lim1, Jun-Kyu Suh2, JinHee Kim3,4, Soyoung Lee3,4, Sungwoo Hong3,4 and Soon-Sun Hong1

1 College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea

2 National Research Center for Sexual Medicine, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea

3 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Republic of Korea

4 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

* These authors contributed equally to this work


Soon-Sun Hong, email:

Sungwoo Hong, email:

Keywords: HS-543, Bcr-Abl, T315I, Chronic Myeloid Leukemia

Received: August 04, 2014 Accepted: December 01, 2014 Published: December 02, 2014


Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathway in a dose-dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and cleaved caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing that of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathway in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.

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