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.
- 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: [email protected].
- 5. College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address: [email protected].
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.