Send to

Choose Destination
Cancer Res. 2019 Jul 16. pii: canres.1236.2019. doi: 10.1158/0008-5472.CAN-19-1236. [Epub ahead of print]

Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-mediated Targeted Protein Degradation.

Author information

Molecular, Cellular and Developmental Biology, Yale University.
Department of Cell, Developmental & Cancer Biology, knight Cancer Institute, Oregon Health & Science University.
Knight Cancer Institute, Division of Hematology and Medical Oncology, Howard Hughes Medical Institute / Oregon Health & Science University.
Knight Cancer Institute, Oregon Health & Science University.
OHSU Knight Cancer Institute, OHSU & Howard Hughes Medical Institute.
Molecular, Cellular, & Dev Biology, Yale University


While the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis targeting chimera (PROTACs) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel Lindau (VHL), resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared to diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1-dependent drug resistance, and warrants further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center