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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance
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Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance

机译：对两种临床活性BCR-ABL激酶抑制剂的比较分析揭示了构象特异性结合在耐药中的作用

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摘要

Structural studies suggest that most point mutations in the BCR-ABL kinase domain cause resistance to the ABL kinase inhibitor imatinib by impairing the flexibility of the kinase domain, restricting its ability to adopt the inactive conformation required for optimal imatinib binding, rather than by directly interfering with drug contact residues. BMS-354825, currently in clinical development for imatinib-resistant chronic myelogenous leukemia, is a dual SRC/ABL kinase inhibitor that binds ABL in both the active and inactive conformation. To examine the potential role of confor-mational binding properties in drug resistance, we mapped the mutations in BCR-ABL capable of conferring resistance to BMS-354825. Through saturation mutagenesis, we identified 10 such BCR-ABL mutations, 8 of which occurred at drug contact residues. Some mutants were unique to BMS-354825, whereas others also conferred imatinib resistance. Remarkably, the identity of the amino acid substitution at either of two contact residues differentially affects sensitivity to imatinib or BMS-354825. The combination of imatinib plus BMS-354825 greatly reduced the recovery of drug-resistant clones. Our findings provide further rationale for considering kinase conformation in the design of kinase inhibitors against cancer targets.
机译：结构研究表明，BCR-ABL激酶结构域中的大多数点突变都会通过削弱激酶结构域的柔韧性，限制其采用最佳伊马替尼结合所需的非活性构象的能力而不是直接干扰而导致对ABL激酶抑制剂伊马替尼的耐药性与药物接触残留物。 BMS-354825是目前在临床上开发的对伊马替尼耐药的慢性粒细胞性白血病，它是一种双重SRC / ABL激酶抑制剂，可在活性和非活性构象中结合ABL。为了检查构象结合特性在耐药中的潜在作用，我们绘制了能够赋予BMS-354825耐药性的BCR-ABL中的突变。通过饱和诱变，我们确定了10个此类BCR-ABL突变，其中8个发生在药物接触残基上。一些突变体是BMS-354825独有的，而另一些也赋予了伊马替尼耐药性。值得注意的是，两个接触残基中任一氨基酸残基的身份差异会影响对伊马替尼或BMS-354825的敏感性。伊马替尼加BMS-354825的组合大大降低了耐药克隆的回收率。我们的发现为在设计针对癌症靶标的激酶抑制剂时考虑激酶构象提供了进一步的理论依据。

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