MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation
MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation
复制标题
DOI：
10.1182/blood-2006-05-025049
复制
发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Freedman, Steven J.
中科院分区：
文献类型：
--
作者：
Giles, Francis J.;Cortes, Jorge;Freedman, Steven J.
MK-0457 (VX-680) 是一种小分子极光激酶 (AK) 抑制剂，具有临床前抗白血病活性。 T315I BCR-ABL 突变介导对伊马替尼、尼罗替尼和达沙替尼的耐药性。 MK-0457 对表达野生型或突变 BCR-ABL（包括 T315I BCR-ABL 突变）的细胞具有体外活性。三名患有 T315I abl 突变的慢性粒细胞白血病 (CML) 或费城染色体 (Ph) 阳性急性淋巴细胞白血病 (ALL) 的患者对 MK-04547 剂量取得了临床反应，且与不良事件无关。较高的 MK-0457 剂量水平与白血病细胞中的临床反应和 CrkL 磷酸化下调相关。 AK 抑制在这些临床反应中的可能作用需要进一步研究。目前报告的病例是首次观察到激酶抑制剂针对 T315I 表型的临床活性。在 3 名 T315I 表型难治性 CML 或 Ph 阳性 ALL 患者中观察到 MK-0457 剂量的反应，且没有明显的髓外毒性，这一结果非常令人鼓舞。
MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor with preclinical antileukemia activity. The T315I BCR-ABL mutation mediates resistance to imatinib, nilotinib, and dasatinib. MK-0457 has in vitro activity against cells expressing wildtype or mutated BCR-ABL, including the T315I BCR-ABL mutation. Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events. Higher MK-0457 dose levels were associated with clinical responses and down-regulation of CrkL phosphorylation in leukemia cells. The possible role of AK inhibition in these clinical responses requires further investigation. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I phenotype. The observation of responses in 3 patients with T315I phenotype-refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.