GMB-475

SKU: orb1298891

Description

GMB-475 is a PROTAC-based degrader that recruits the VHL E3 ligase to ubiquitinate and eliminate the BCR-ABL1 oncoprotein, overcoming kinase inhibitor resistance. It is a research tool for investigating targeted protein degradation in models of chronic myeloid leukemia (CML), both in cellular and preclinical in vivo studies.

Research Area

Cardiovascular Research, Cell Biology, Epigenetics & Chromatin, Pharmacology & Drug Discovery, Signal Transduction, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 2490599-18-1
• MW: 861.93
• Purity: >99.99% (May vary between batches)
• Formula: C₄₃H₄₆F₃N₇O₇S
• SMILES: Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)COCCOc2ccc(cc2)-c2cc(Nc3ccc(OC(F)(F)F)cc3)ncn2)C(C)(C)C)cc1
• Target: Apoptosis,Bcr-Abl,PROTACs,E3 Ligase Ligand-Linker Conjugates,JAK,STAT
• Solubility: DMSO:245 mg/mL (284.25 mM);10% DMSO+40% PEG300+5% Tween 80+45% Saline:5 mg/mL (5.8 mM)

Bioactivity

• 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.

Storage & Handling

• Storage: store at low temperature,keep away from direct sunlight | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

PROTACs, GMB 475, GMB475, GMB-475, Inhibitor, inhibit, Apoptosis, Bcr-Abl1, Bcr-Abl, BcrAbl

Compound Identifiers

PubChem CID

139600282