N-Degron PROTACs as a Potential Therapeutic Approach for Chronic Myeloid Leukemia.

Abstract

Many oncoproteins are important therapeutic targets because of their critical role in inducing rapid cell proliferation, which represents one of the salient hallmarks of cancer. Chronic Myeloid Leukemia (CML) is a cancer of hematopoietic stem cells that is caused by the oncogene BCR-ABL1. BCR-ABL1 encodes a constitutively active tyrosine kinase protein that leads to the uncontrolled proliferation of myeloid cells, which is a hallmark of CML. A current therapeutic approach for the treatment of CML, Tyrosine Kinase Inhibitors (TKIs), effectively inactivates BCR-ABL1 kinase activity; however, drug resistance to TKIs limits the long-term potential for this treatment. Proteolysis Targeting Chimera (PROTAC) has emerged as a promising pharmacological approach for degrading, rather than inhibiting, targeted proteins by harnessing the ubiquitin-proteosome system. This process involves tagging a Protein of Interest (POI) with ubiquitin by the E3 ubiquitin ligases, which subsequently target the protein for proteasomal degradation. The N-end rule or the N-degron concept describes the correlation between the metabolic stability of a protein and the biochemical identity of its N-terminal amino acid. A recent work unveiled that N-degron PROTACs could offer a potential treatment for CML by targeting and degrading BCR-ABL1 proteins. Herein, we present the molecular and biochemical implications for targeting chronic myeloid leukemia.