1. Product Overview
GMB-475 (CAS 2490599-18-1) is a sophisticated VHL-based PROTAC (Proteolysis Targeting Chimera) engineered for the specific degradation of the BCR-ABL1 oncogenic fusion protein. Unlike conventional ATP-competitive inhibitors, GMB-475 employs an event-driven pharmacology model, utilizing the cell's endogenous ubiquitin-proteasome system (UPS) to eliminate target proteins. It is a critical investigational tool for researchers focusing on overcoming tyrosine kinase inhibitor (TKI) resistance in Chronic Myeloid Leukemia (CML) and other hematological malignancies.
2. Key Features and Advantages
• Superior Resistance Overcoming: Designed to degrade both wild-type and mutant forms of BCR-ABL1, effectively bypassing gatekeeper mutations (e.g., T315I) and other conformational changes that confer resistance to small molecule inhibitors.
• Dual-Mechanism Engagement: Acts as a heterobifunctional molecule; one end binds the ABL1 myristoyl pocket (allosteric site), while the other recruits the Von Hippel-Lindau (VHL) E3 ubiquitin ligase, facilitating proximity-induced ubiquitination.
• High Catalytic Efficiency: Operates via a sub-stoichiometric mode of action, meaning a single degrader molecule can catalyze the degradation of multiple target proteins, potentially allowing for lower effective doses and sustained effects.
• Exceptional Selectivity Profile: Engineered to minimize off-target degradation, ensuring that experimental results are specifically attributable to BCR-ABL1 modulation.
• Research Grade Quality: Manufactured under strict quality control standards, guaranteeing high batch-to-batch consistency for reproducible experimental outcomes.
3. Main Applications
• Cancer Biology: Extensively used in cell viability assays (MTT/XTT) and colony formation assays using CML cell lines such as K562 and Ba/F3-BCR-ABL1.
• Mechanism of Action Studies: Ideal for investigating the dynamics of protein degradation, including DC50 (half-maximal degrading concentration) and Dmax (maximum degradation) determination via Western Blotting.
• Drug Resistance Modeling: Facilitates the study of resistance mechanisms in TKI-resistant cell lines, providing insights into alternative therapeutic strategies.
• In Vivo Xenograft Models: Suitable for preclinical pharmacokinetic/pharmacodynamic (PK/PD) studies in murine models to evaluate tumor regression efficacy.
• Biochemical Assays: Used in co-immunoprecipitation (Co-IP) experiments to confirm ternary complex formation between the target protein, PROTAC, and the E3 ligase.
4. Technical Specifications
5. Storage and Handling
• Reconstitution: To prepare a stock solution, gently warm the vial to room temperature before opening. Centrifuge briefly to collect material at the bottom. Dissolve in anhydrous DMSO to achieve a clear solution.
• Aliquoting: To avoid degradation caused by repeated freeze-thaw cycles, aliquot the reconstituted solution into single-use volumes immediately after preparation.
• Long-term Storage: Store the powder in a desiccator at -20°C under an inert atmosphere (Argon or Nitrogen) if possible. Protect rigorously from light and moisture.
• Handling Precautions: Use only in a well-ventilated laboratory fume hood. Wear appropriate chemical-resistant gloves (e.g., nitrile) and safety glasses. Minimize exposure to oxidizing agents.
6. Safety Overview
GMB-475 is classified for Laboratory Research Use Only (LRUO). It is not approved for human administration, food additives, drugs, medical devices, or household use. Potential hazards include acute toxicity upon ingestion or inhalation and skin/eye irritation. In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. Dispose of contents in accordance with local, regional, and national regulations for chemical waste. Always refer to the accompanying Safety Data Sheet (SDS) for detailed toxicological data and emergency procedures.
