The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1
The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1
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DOI：
10.1038/nature21702
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发表时间：
2017-03-30
期刊：
影响因子：
64.8
通讯作者：
Sellers, William R.
中科院分区：
文献类型：
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作者：
Wylie, Andrew A.;Schoepfer, Joseph;Sellers, William R.
慢性粒细胞白血病（CML）是由BCR-ABL 1融合癌蛋白的活性驱动的。ABL 1激酶抑制剂改善了CML患者的临床结局，超过80%接受伊马替尼治疗的患者存活超过10年（1）。第二代ABL 1激酶抑制剂在既往未经治疗和伊马替尼耐药的CML 2患者中诱导更有效的分子应答。在慢性期CML患者中进行的研究表明，约50%达到并维持不可检测的BCR-ABL 1转录水平至少2年的患者在停止治疗后仍无疾病（3，4）。在这里，我们描述了ABL 001（asciminib），一种有效的和选择性的变构ABL 1抑制剂，正在CML和费城染色体阳性（Ph+）急性淋巴细胞白血病患者中进行临床开发测试。与催化位点ABL 1激酶抑制剂相反，ABL 001结合ABL 1的肉豆蔻酰口袋，并诱导形成无活性的激酶构象。ABL 001和第二代催化抑制剂具有相似的细胞效力，但具有不同的耐药突变模式，遗传条形码研究揭示了ABL 001和催化抑制剂尼洛替尼之间没有共同耐药的预先存在的克隆群体。与此特征一致，在小鼠中观察到单药治疗的获得性耐药性;然而，ABL 001和尼洛替尼联合治疗可完全控制疾病并根除CML异种移植肿瘤，停止治疗后未复发。
Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years(1). Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML2. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment(3,4). Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.