GMB-475

GMB-475 is a BCR-ABL1 tyrosine kinase degrader based on PROTAC, overcoming BCR-ABL1-dependent drug resistance. GMB-475 targets BCR-ABL1 protein and recruits the E3 ligase Von Hippel Lindau (VHL) .resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein (In Vitro) :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 warrant 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.

2490599-18-1

>98% (HPLC)

In Vitro: DMSO : 250 mg/mL (290.05 mM)

CC1=C (SC=N1) C1=CC=C (CNC (=O) C2CC (O) CN2C (=O) C (NC (=O) COCCOC2=CC=C (C=C2) C2=CC (NC3=CC=C (OC (F) (F) F) C=C3) =NC=N2) C (C) (C) C) C=C1

C43H4F3NOS

861.93

Storage temperature: -20°C. Stability: ≥ 2 years