Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, China.
Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Adv Sci (Weinh). 2022 May;9(13):e2104850. doi: 10.1002/advs.202104850. Epub 2022 Mar 3.
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 Bcr/Abl-R6, is designed by engrafting an MDM2/p53 inhibition peptide sequence onto the Bcr/Abl tetramerization domain. Bcr/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 Bcr/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 Bcr/Abl-R6 is demonstrated to simultaneously induce Bcr/Abl degradation and activate the p53 pathway. Bcr/Abl-R6 has the potential to overcome drug resistance in Ph+ leukemias by multiple mechanisms.
Bcr/Abl 在费城染色体阳性（Ph+）白血病中发挥核心作用，这是由于其组成性激活的 Abl 酪氨酸激酶及其下游途径。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。在此，设计了一种双靶向蛋白水解靶向嵌合体（PROTAC）蛋白药物，称为 Bcr/Abl-R6，它通过将 MDM2/p53 抑制肽序列插入到 Bcr/Abl 四聚化结构域中。Bcr/Abl-R6 携带 Bcr/Abl 靶向序列和 MDM2 结合序列，在 Ph+白血病细胞中作为 PROTAC 药物发挥作用。其双靶向结构表明，Bcr/Abl-R6 的设计目的是针对四聚化结构域而不是 Abl 激酶结构域，因此有可能克服激酶结构域中的耐药性突变。研究表明，Bcr/Abl-R6 能够有效地同时诱导 Bcr/Abl 降解并激活 p53 通路。Bcr/Abl-R6 有可能通过多种机制克服 Ph+白血病的耐药性。
