Gray Nathanael S, Fabbro Doriano
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston MA, USA.
PIQUR Therapeutics AG, Hochbergerstrasse 60C, Basel, Switzerland.
Methods Enzymol. 2014;548:173-88. doi: 10.1016/B978-0-12-397918-6.00007-0.
The development of imatinib, an ATP-competitive inhibitor of the BCR-ABL oncoprotein, has revolutionized the treatment of chronic myelogenous leukemia (CML). Unfortunately, the leukemia eventually becomes resistant imatinib as a result of emergence of cells expressing drug insensitive BCR-ABL mutant proteins. This has motivated the development of several next-generation ATP-competitive drugs. This chapter describes the discovery and development of a complementary strategy involving inhibiting BCR-ABL by targeting an allosteric binding site. Compounds that bind to the myristate-binding pocket of BCR-ABL are able to induce formation of an "inactive" state and are able to overcome resistance mutations located in the ATP-binding pocket including the recalcitrant T315I "gatekeeper" mutation. Myristate-pocket inhibitors are also able to function synergistically with ATP-competitive inhibitors in cellular and murine models of CML and this dual inhibitory strategy is currently being investigated in the clinic.
伊马替尼是一种BCR-ABL癌蛋白的ATP竞争性抑制剂，它的出现彻底改变了慢性粒细胞白血病（CML）的治疗方式。不幸的是，由于表达对药物不敏感的BCR-ABL突变蛋白的细胞出现，白血病最终会对伊马替尼产生耐药性。这促使了几种下一代ATP竞争性药物的研发。本章描述了一种互补策略的发现和发展，该策略通过靶向变构结合位点来抑制BCR-ABL。与BCR-ABL的肉豆蔻酸结合口袋结合的化合物能够诱导形成“无活性”状态，并能够克服位于ATP结合口袋中的耐药突变，包括顽固的T315I“守门人”突变。在CML的细胞和小鼠模型中，肉豆蔻酸口袋抑制剂也能够与ATP竞争性抑制剂协同发挥作用，目前这种双重抑制策略正在临床中进行研究。
