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

Abstract

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.