Targeting BCR-ABL Protein Degradation: Conjugation of ABL Kinase Inhibitors and IAP Ligands for CML Therapy

In certain cancer cells, chromosomal translocation leads to the production of abnormal fusion proteins, such as BCR-ABL, which is found in chronic myelogenous leukemia (CML). While ABL tyrosine kinase inhibitors like imatinib and dasatinib have shown significant therapeutic benefits, the development of drug resistance can complicate long-term treatment. An alternative strategy involves reducing the levels of the BCR-ABL protein.

Researchers have developed a novel protein knockdown system using hybrid molecules known as Specific and Non-genetic inhibitor of apoptosis protein-dependent Protein Erasers (SNIPER). These SNIPERs are engineered to trigger the ubiquitylation and subsequent proteasomal degradation of target proteins. Recently, several SNIPER(ABL) molecules targeting the BCR-ABL protein have been created.

In this study, the researchers experimented with different combinations of ABL inhibitors and IAP ligands, optimizing the linker for enhanced protein knockdown activity. The most effective compound, SNIPER(ABL)-39, combines dasatinib with an IAP ligand derivative, LCL161, connected by a polyethylene glycol (PEG) linker. SNIPER(ABL)-39 demonstrated a strong ability to degrade the BCR-ABL protein.

Mechanistic studies indicated that both cellular IAP1 and XIAP contribute to the degradation process. Additionally, SNIPER(ABL)-39 was found to inhibit the phosphorylation of STAT5 and CrkL, and it effectively suppressed the growth of BCR-ABL-positive CML cells. These findings suggest that SNIPER(ABL)-39 may represent a promising new degradation-based anti-cancer agent for BCR-ABL-positive CML.