Kill Two Birds with One Stone: A Multifunctional Dual‐Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome‐Positive Leukemia

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 (PMI)Bcr/Abl‐R6, is designed by engrafting an MDM2/p53 inhibition peptide sequence onto the Bcr/Abl tetramerization domain. (PMI)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 (PMI)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 (PMI)Bcr/Abl‐R6 is demonstrated to simultaneously induce Bcr/Abl degradation and activate the p53 pathway. (PMI)Bcr/Abl‐R6 has the potential to overcome drug resistance in Ph+ leukemias by multiple mechanisms.