GMB-475

SKU: orb1940247

Description

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.

Key Properties

• CAS Number: 2490599-18-1
• MW: 861.93
• Purity: >98% (HPLC)
• Formula: C₄₃H₄F₃NOS
• SMILES: 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
• Target: Bcr-Abl
• Solubility: In Vitro: DMSO : 250 mg/mL (290.05 mM)

Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

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Gene Symbol

Bcr-Abl