Single amino acid-based PROTACs trigger degradation of the oncogenic kinase BCR-ABL in chronic myeloid leukemia (CML)

Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system (UPS) is emerging as a potent anti-cancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein Bcr-Abl, an oncogenic kinase that drives the progression of chronic myeloid leukemia (CML). We find that the reduction level of Bcr-Abl can be easily adjusted by substituting different Amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of Bcr-Abl protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing Bcr-Abl in vitro, and blunted tumor growth in a K562 xenograft tumor model in vivo. The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo, our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.

N-end rule; PROTAC; amino acid; cancer; drug design; leukemia; protein degradation; ubiquitin.