Kill Two Birds with One Stone: A Multifunctional Dual-Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome-Positive Leukemia.
Kill Two Birds with One Stone: A Multifunctional Dual-Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome-Positive Leukemia.
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DOI：
10.1002/advs.202104850
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发表时间：
2022-05
期刊：
影响因子：
15.1
通讯作者：
Niu, Fan
中科院分区：
文献类型：
--
作者：
Ma, Bohan;Feng, Hui;Feng, Chao;Liu, Yi;Zhang, Hailing;Wang, Jincheng;Wang, Wenjuan;He, Pengcheng;Niu, Fan
由于bcr/abl酪氨酸激酶及其下游通路的结构性激活，bcr/abl在Ph+白血病中起着核心作用。目前，酪氨酸激酶抑制剂对伊马替尼耐药患者的临床治疗受到耐药性和不良反应的严重限制。在本研究中，通过将MDM2/p53抑制肽序列连接到bcr/abl四聚结构域上，设计了一种双靶向蛋白水解靶向嵌合体(PROTAC)蛋白药物PMIBcr/Abl-R6。PMIBcr/Abl-R6具有bcr/abl靶向序列和MDM2结合序列，在Ph+白血病细胞中作为PROTAC药物。它的双靶向结构表明PMIBcr/Abl-R6设计针对四聚化结构域而不是Abl激活域，因此具有克服激活域耐药突变的潜力。PMIBcr/Abl-R6能有效地同时诱导bcr/abl降解和激活P53通路。PMIBcr/Abl-R6有可能通过多种机制克服Ph+白血病的耐药性。对伊马替尼耐药的费城染色体阳性(Ph+)白血病的治疗仍然是一个挑战。PMIBcr/Abl-R6是一种设计的蛋白质PROTAC(蛋白质降解靶向嵌合体)，它同时针对bcr/abl四聚化和p53/mdm2相互作用，这两种作用都很难被小分子“下药”。PMIBcr/Abl-R6可诱导bcr/abl降解，而不考虑异构体和耐药相关突变，并激活P53通路，为蛋白质相互作用靶点提供不同的药物设计策略。
The Bcr/Abl plays a central role in Philadelphia chromosome‐positive (Ph+) leukemia because of the constitutively activated Abl tyrosine kinase and its downstream pathways. Currently, the clinical treatment of imatinib‐resistant patients with tyrosine kinase inhibitors is severely limited by drug resistance and adverse effects. Herein, a dual‐targeting proteolysis‐targeting chimera (PROTAC) protein drug, termed PMIBcr/Abl‐R6, is designed by engrafting an MDM2/p53 inhibition peptide sequence onto the Bcr/Abl tetramerization domain. PMIBcr/Abl‐R6, harboring a Bcr/Abl targeting sequence and an MDM2 binding sequence, acts as a PROTAC drug in Ph+ leukemia cells. Its dual‐targeting constitution suggests that PMIBcr/Abl‐R6 designs to target the tetramerization domain instead of the Abl kinase domain, therefore has the potential to overcome drug resistance mutations in the kinase domain. The efficient ability of PMIBcr/Abl‐R6 is demonstrated to simultaneously induce Bcr/Abl degradation and activate the p53 pathway. PMIBcr/Abl‐R6 has the potential to overcome drug resistance in Ph+ leukemias by multiple mechanisms. Imatinib‐resistant Philadelphia chromosome‐positive (Ph+) leukemia treatment remains a challenge. PMIBcr/Abl‐R6, a designed protein PROTAC (proteolysis‐targeting chimera), targets simultaneously Bcr/Abl tetramerization and p53/MDM2 interaction, both hardly “druggable” by small molecules. PMIBcr/Abl‐R6 induces Bcr/Abl degradation, despite isoforms and resistance‐related mutations, and activates p53 pathway, providing a different drug design strategy for protein–protein interaction targets.
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影响因子：
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作者：
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