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亚克西替尼有效地抑制BCR-ABL1 (T315I) 具有明显的结合形状

Tea Pemovska¹, Eric Johnson², Mika Kontro³

¹Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland.

|February 18, 2015

概括

在白血病中,阿克西替尼有效向耐药BCR-ABL1 T315I突变. 这种重新设计的抗血管性药物为耐药慢性髓性白血病和急性淋巴细胞白血病患者提供了新的治疗选择.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

BCR-ABL1融合基因驱动慢性髓性白血病和一些成人急性淋巴细胞白血病.
ABL1激酶抑制剂提高了生存率,但获得的耐药性,特别是T315I守门员突变,仍然是一个重大的临床挑战.
该T315I突变赋予了对大多数批准的ABL1抑制剂的耐药性,波纳替尼是例外,但有毒性问题.

研究的目的:

为了确定BCR-ABL1 T315I突变白血病的有效抑制剂.
为了研究艾克西尼布的潜在重新用途,一个VEGFR氨酸激酶抑制剂,T315I突变白血病.

主要方法:

患者衍生细胞的药物敏感性和耐药性概况的全面分析.
对阿克西尼布与BCR-ABL1 (T315I) 的结合进行结构分析.
一个T315I慢性髓性白血病患者的临床治疗,使用阿克西替尼.

主要成果:

亚克西替尼在生物化学和细胞水平上都表现出强大的BCR-ABL1 (T315I) 抑制.
结构分析显示,阿克西替尼通过突变选择性模式与ABL1 (T315I) 的活性构造结合.
在T315I慢性髓性白血病患者中,使用阿克西替尼治疗导致T315I阳性细胞的快速减少.

结论:

阿克西替尼是T315I突变BCR-ABL1驱动白血病的选择性和有效抑制剂,提供了一种新的治疗策略.
T315I突变诱导了ABL1的形状变化,有利于亚西替尼的结合.
对抗性白血病的阿克西替尼的重新应用强调了对患者细胞进行全面药物测试的价值,以确定新的治疗机会.

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