College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
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.
Cancer Lett. 2014 Jun 28;348(1-2):50-60. doi: 10.1016/j.canlet.2014.03.012. Epub 2014 Mar 18.
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.
伊马替尼是一种选择性的断点簇区-Abelson（BCR-ABL）酪氨酸激酶抑制剂（TKI），它显著改善了慢性髓性白血病（CML）患者的预后。然而，BCR-ABL 激酶结构域的 T315I 基因突变已被证明对伊马替尼具有耐药性。在本研究中，我们合成了一种新型的 BCR-ABL 抑制剂 HS-438，并在体外和体内鉴定了其抗白血病作用。我们发现 HS-438 强烈抑制野生型 BCR-ABL（BaF3/WT）细胞以及对伊马替尼耐药的 T315I 突变型 BCR-ABL（BaF3/T315I）细胞中 BCR-ABL 信号通路的表达。HS-438 诱导细胞周期停滞，特别是在 G0/G1 细胞周期阶段，并诱导细胞凋亡。在 BaF3/T315I 异种移植模型中，HS-438 显著延缓了肿瘤生长，与伊马替尼不同。总之，我们认为 HS-438 可能是一种新型的候选药物，具有靶向 BCR-ABL 的治疗潜力，并能克服 CML 患者对伊马替尼的耐药性。
