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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Proteolysis-targeting chimera (PROTAC) technology is a promising anticancer strategy.
• Efficient modulation of target protein degradation remains a significant challenge in PROTAC development.

Purpose of the Study:

• To develop a novel, single amino acid-based PROTAC for targeted degradation of the BCR-ABL fusion protein.
• To investigate the modulation of target degradation levels by varying amino acid sequences and linker lengths.
• To evaluate the in vitro and in vivo efficacy of the N-end rule pathway-based PROTAC.

Main Methods:

• Utilized a single amino acid-based PROTAC design incorporating the shortest degradation signal sequence for N-end rule E3 ubiquitin ligases.
• Investigated the degradation of BCR-ABL protein by substituting different amino acids and employing a single PEG linker.
• Assessed the efficacy of the PROTAC in inhibiting K562 cell growth in vitro and tumor growth in a K562 xenograft model in vivo.

Main Results:

• Achieved effective degradation of BCR-ABL protein via the N-end rule pathway.
• Demonstrated adjustable BCR-ABL reduction levels by amino acid substitution.
• Showcased efficient inhibition of K562 cell growth in vitro and blunted tumor growth in vivo.
• The developed PROTAC exhibited a lower effective concentration and smaller molecular size.

Conclusions:

• The N-end rule pathway-based PROTAC effectively degrades BCR-ABL, leading to cancer cell growth inhibition.
• This study expands the available degradation pathways for PROTACs and offers a modular approach for targeted protein degradation.
• The developed PROTAC technology shows potential for broader applications in cancer therapy.