Overriding imatinib resistance with a novel ABL kinase inhibitor
Overriding imatinib resistance with a novel ABL kinase inhibitor
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DOI：
10.1126/science.1099480
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发表时间：
2004-07-16
期刊：
影响因子：
56.9
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Shah, NP;Tran, C;Sawyers, CL
慢性粒细胞白血病 (CML) 对 ABL 激酶抑制剂伊马替尼（STI571 或格列卫）的耐药性是通过选择含有干扰药物结合的 BCR-ABL 激酶结构域点突变的肿瘤细胞而发生的。晶体学研究预测，大多数伊马替尼耐药突变体应该对结合 ABL 的抑制剂保持敏感，但构象要求不太严格。 BMS-354825 是一种口服生物可利用的 ABL 激酶抑制剂，相对于伊马替尼，其效力增加了两倍，并且保留了针对 15 种伊马替尼耐药 BCR-ABL 突变体中的 14 种的活性。 BMS-354825 可延长患有 BCR-ABL 驱动疾病的小鼠的存活时间，并抑制伊马替尼敏感和伊马替尼耐药 CML 患者的 BCR-ABL 阳性骨髓祖细胞的增殖。这些数据说明了对激酶抑制剂耐药性的分子洞察如何指导第二代靶向疗法的设计。
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.