Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I
Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I
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DOI：
10.1182/blood-2007-09-113175
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Bruemmendorf, Tim H.
中科院分区：
文献类型：
--
作者：
Gontarewicz, Artur;Balabanov, Stefan;Bruemmendorf, Tim H.
BCR-ABL结构域突变介导的伊马替尼耐药（IM）的出现已成为慢性髓性白血病（CML）治疗的主要挑战。在这里，我们报道了一种新的小分子抑制剂PHA-739358的研究，它选择性地靶向Bcr-Abl和Aurora激酶a到C. PHA-739358对广泛的人类Bcr-Abl阳性和阴性细胞系以及对异位表达野生型（wt）或im抗性Bcr-Abl突变体（包括T315I）的小鼠BaF3细胞显示出强大的抗增殖和促凋亡活性。IM和PHA739358在对IM几乎完全耐药的白血病细胞系中具有药理协同作用。PHA-739358显著降低了Aurora B活性标志物组蛋白H3和Bcr-Abl下游靶点CrkL的磷酸化，表明PHA-739358通过联合抑制Bcr-Abl和Aurora激酶起作用。此外，PHA-739358在来自未经治疗的CML患者和来自慢性期或母细胞危象的im抵抗个体（包括携带T315I突变的个体）的CD34（+）细胞中观察到强大的抗增殖作用。因此，PHA-739358代表了一种治疗耐药bcr - abl阳性白血病的新策略，包括那些携带T315I突变的白血病。研究这种化合物在耐药CML中的临床试验最近已经启动。
The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34(+) cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.