Allosteric inhibition of BCR-ABL
Allosteric inhibition of BCR-ABL
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DOI：
10.4161/cc.9.18.13232
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发表时间：
2010-09
期刊：
影响因子：
4.3
通讯作者：
A. Quamrul Hassan;Sreenath V. Sharma;M. Warmuth
中科院分区：
文献类型：
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作者：
A. Quamrul Hassan;Sreenath V. Sharma;M. Warmuth
激酶活性调节受损可导致多种疾病，包括癌症。因此，抑制激酶活性被认为是一种有吸引力的抗癌治疗策略。BCR-ABL靶向治疗的成功已经得到了很好的证明，伊马替尼在慢性粒细胞白血病(CML)中特异性地抑制激酶活性，具有令人印象深刻的药理反应。然而，由于获得性耐药性的出现，激酶抑制剂作为癌症治疗药物的成功正受到临床的挑战。目前市场上的大多数激酶抑制剂都是ATP竞争性的。人们一直在努力开发具有新作用模式的激酶抑制剂。在这篇综述中，我们重点介绍了通过与远离活性部位的位置结合来抑制蛋白激酶活性的“变构蛋白激酶抑制剂”的研究进展。我们集中于最近针对bcr-abl的努力，为此，在开发具有良好治疗活性的变构抑制剂方面取得了重大进展，特别是在克服临床获得的对第一代ATP竞争性激酶抑制剂的耐药性突变的背景下。
Impaired regulation of kinase activity can lead to a variety of diseases, including cancer. Inhibition of kinase activity has, therefore, been considered an attractive anti-cancer therapeutic strategy. The success of targeted therapy with kinase inhibitors has been well documented with BCR-ABL, where imatinib specifically inhibits kinase activity with impressive pharmacological responses in chronic myelogenous leukemia (CML). However, the success of kinase inhibitors as cancer therapeutics is being challenged clinically by the emergence of acquired resistance. Most kinase inhibitors available today are ATP-competitive. There have been efforts to develop kinase inhibitors with new modes of action. In this review, we highlight the development of 'allosteric kinase inhibitors' that inhibit kinase activity by binding to a site remote from the active site of the kinase. We focus on recent efforts directed towards BCR-ABL, for which, significant progress has been made to develop allosteric inhibitors with promising therapeutic activity, especially in the context of overcoming clinically acquired resistance mutations to the first generation of ATP-competitive kinase inhibitors.