Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8435620 | Cancer Letters | 2014 | 11 Pages |
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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Cancer Research
Authors
Sun-Mi Yun, Kyung Hee Jung, Soo Jung Kim, Zhenghuan Fang, Mi Kwon Son, Hong Hua Yan, Hyunseung Lee, JinHee Kim, Sanghye Shin, Sungwoo Hong, Soon-Sun Hong,