Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the BCR-ABL fusion gene that produces the constitutively active protein, BCR-ABL. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the BCR-ABL kinase domains. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant BCR-ABL. S116836 was efficacious in BaF3 cells with WT or T315I mutated BCR-ABL genotypes. S116836 inhibits the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant BCR-ABL without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I BCR-ABL mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

中文翻译：

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新型BCR-ABL T315I抑制剂对慢性粒细胞白血病的临床前开发。

慢性粒细胞性白血病（CML）是一种骨髓增殖性肿瘤，主要是由于BCR-ABL融合基因的存在，该基因会产生组成型活性蛋白BCR-ABL。伊马替尼是BCR-ABL靶向药物，是治疗CML的一线药物。对伊马替尼的抗药性是BCR-ABL激酶结构域突变的结果。在这项研究中，我们评估了新型BCR-ABL抑制剂S116836对野生型（WT）和T315I突变BCR-ABL的抗癌功效。S116836在具有WT或T315I突变的BCR-ABL基因型的BaF3细胞中有效。S116836在BaF3 / WT和BaF3 / T315I细胞中抑制BCR-ABL的磷酸化及其下游信号传导。从机制上讲，S116836将细胞停在细胞周期的G0 / G1期，诱导细胞凋亡，增加ROS的产生，并降低BaF3 / WT和BaF3 / T315I细胞中GSH的产生。此外，在小鼠肿瘤异种移植物中，S116836显着抑制表达WT或T315I突变体BCR-ABL的肿瘤的生长和体积，而不会引起明显的心脏毒性。总体而言，我们的结果表明S116836显着抑制了对伊马替尼耐药的T315I BCR-ABL突变，并且可能成为治疗对伊马替尼耐药的CML患者的新型药物。