1. Product Overview
Luxdegalutamide, also known as ARV-766 (CAS No. 2750830-09-0), is an advanced, orally bioavailable Proteolysis Targeting Chimera (PROTAC) specifically designed to degrade the Androgen Receptor (AR). With a molecular weight of 807.95 g/mol, this complex molecule comprises a high-affinity AR ligand, a rationally designed linker, and a Von Hippel-Lindau (VHL) E3 ubiquitin ligase recruitment moiety. Unlike traditional AR antagonists that merely block receptor function, ARV-766 induces ubiquitin-mediated proteasomal degradation of AR, effectively suppressing signaling even in the presence of clinically relevant AR point mutations (e.g., W742L, H874Y, F877L) and splice variants (e.g., AR-V7) that confer resistance to enzalutamide and apalutamide. Currently in clinical development for metastatic castration-resistant prostate cancer (mCRPC), Luxdegalutamide serves as a critical chemical probe for studying AR dependency and overcoming resistance mechanisms in prostate oncology.
2. Key Features and Advantages
• Potent AR Degradation: Achieves DC50 values in the low nanomolar range (single-digit to low double-digit nM) in LNCaP and enzalutamide-resistant cell lines, leading to robust AR protein depletion.
• Overcomes Clinical Resistance: Effectively degrades clinically relevant AR mutants (W742L, H874Y, F877L) and splice variants (AR-V7) that render current standard-of-care anti-androgens ineffective.
• Oral Bioavailability: Demonstrates excellent oral pharmacokinetics in preclinical species, supporting its clinical translation and utility in in vivo xenograft models.
• Favorable Physicochemical Properties: Despite its large molecular size, it maintains acceptable solubility and permeability profiles suitable for both cell culture and animal studies.
• Research-Grade Quality: Supplied at ≥98% purity (HPLC), ensuring consistent and reliable performance in biochemical assays and in vivo efficacy studies.
3. Main Applications
• Prostate Cancer Research: Primary tool for investigating AR degradation in castration-resistant prostate cancer (CRPC), particularly in models resistant to enzalutamide, abiraterone, and darolutamide.
• Mechanisms of Resistance: Studying how AR structural alterations (mutations and splice variants) mediate resistance to hormonal therapies and how PROTACs circumvent these barriers.
• PROTAC Technology Development: Serving as a premier reference molecule for designing next-generation AR degraders, optimizing linker chemistry, and exploring new E3 ligase recruiters.
• Drug Combination Studies: Evaluating synergy with PI3K/AKT inhibitors, PARP inhibitors, or chemotherapeutics in AR-dependent and AR-independent tumor models.
• Androgen Signaling Dissection: Monitoring the downstream effects of complete AR removal on gene expression profiles, cell proliferation, and apoptosis in prostate cell lines.
4. Technical Specifications
5. Storage and Handling
• Powder Storage: Store at -20°C in a tightly sealed container, protected from light and desiccated. Stable for up to 3 years under these conditions. Avoid storage at elevated temperatures or high humidity.
• Solution Storage: Prepare stock solutions in anhydrous DMSO (concentration ≤ 25 mM). Aliquot into single-use volumes to prevent repeated freeze-thaw cycles. Store aliquots at -80°C for long-term (up to 6 months) or -20°C for short-term (up to 1 month).
• Handling: Allow the sealed vial to warm to room temperature before opening to prevent moisture condensation. Weigh powder in a dry, inert atmosphere or fume hood. Sonicate DMSO stock solutions briefly if precipitation occurs.
• In Vivo Formulation: Due to poor aqueous solubility, formulate in appropriate vehicles such as 10% DMSO with 90% saline, or corn oil/Tween 80 mixtures for oral gavage, ensuring complete solubilization via sonication prior to dosing.
6. Safety Overview
• Intended Use: For laboratory research use only. Not for human or veterinary therapeutic, diagnostic, food, or cosmetic applications.
• Hazard Profile: Classified as a combustible organic solid (WGK Germany 3). As a bioactive PROTAC molecule, it may exhibit cytotoxicity and endocrine-modulating activity in biological systems.
• Precautions: Wear nitrile gloves, safety goggles, and a laboratory coat. Avoid inhalation of dust, contact with skin or eyes, and ingestion. Handle in a well-ventilated area or chemical fume hood.
• Disposal: Dispose of as hazardous organic chemical waste in accordance with local environmental regulations. Do not discharge into drains or the natural environment.
• Note: Include appropriate vehicle controls (DMSO/saline or corn oil) in all cell-based and animal experiments to account for solvent effects and monitor for off-target toxicity.
