• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation
【24h】

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

机译：阿昔替尼以独特的结合构象有效抑制BCR-ABL1（T315I）

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

很多慢性骨髓性白血病(CMLs)和急性淋巴细胞白血病(ALLs)都是由8CR-ABL融合基因造成的。用选择性激酶抑制剂以BCR-ABL为目标进行治疗使CMLS血病的治疗发生了革命性变化，但患者经常会对治疗产生抵抗力，原因经常是由于BCR-ABL发生了二次突变。在来自CML和ALL患者的初生细胞中对已经被批准上市和仍处在研究阶段的抗癌药物所做的这项大规模筛选中，Krister Wennerberg及同事发现"阿西替尼"（一种被批准用于治疗肾癌的多激酶抑制剂）在来自初发患者的CML和ALL细胞中（包括在具有二次抵抗力突变的细胞中）具有活性。在一位CML患者身上(对这位患者其他所有治疗方案都已用尽)，通过"阿西替尼"的诱导，循环的8CR-ABL转录体水平降低了。这些初步的临床发现显示了将现有药物改变用途用于治疗其他类型癌症所具有的潜力。%The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1 (T315I), at both biochemical and cellular levels, by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
机译：很多慢性骨髓性白血病(CMLs)和急性淋巴细胞白血病(ALLs)都是由8CR-ABL融合基因造成的。用选择性激酶抑制剂以BCR-ABL为目标进行治疗使CMLS血病的治疗发生了革命性变化，但患者经常会对治疗产生抵抗力，原因经常是由于BCR-ABL发生了二次突变。在来自CML和ALL患者的初生细胞中对已经被批准上市和仍处在研究阶段的抗癌药物所做的这项大规模筛选中，Krister Wennerberg及同事发现"阿西替尼"（一种被批准用于治疗肾癌的多激酶抑制剂）在来自初发患者的CML和ALL细胞中（包括在具有二次抵抗力突变的细胞中）具有活性。在一位CML患者身上(对这位患者其他所有治疗方案都已用尽)，通过"阿西替尼"的诱导，循环的8CR-ABL转录体水平降低了。这些初步的临床发现显示了将现有药物改变用途用于治疗其他类型癌症所具有的潜力。%The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1 (T315I), at both biochemical and cellular levels, by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

著录项

  • 来源
    《Nature》 |2015年第7541期|102-105A2|共5页
  • 作者

    Tea Pemovska; Eric Johnson; Mika Kontro; Gretchen A. Repasky; Jeffrey Chen; Peter Wells; Ciaran N. Cronin; Michele McTigue; Olli Kallioniemi; Kimmo Porkka; Brion W. Murray; Krister Wennerberg;

  • 作者单位

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

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA;

    Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland;

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

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA ,Wellspring Biosciences LLC, La Jolla, California 92037, USA;

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA;

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA;

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA;

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

    Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland;

    La Jolla Laboratories, Pfizer Worldwide Research & Development, San Diego, California 92121, USA;

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

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号