1. Product Overview
dBRD9 (CAS No. 2170679-45-3) is a potent, cereblon (CRBN)-recruiting PROTAC (Proteolysis Targeting Chimera) designed to induce the selective degradation of bromodomain-containing protein 9 (BRD9), a non-canonical subunit of the BAF (SWI/SNF) chromatin remodeling complex. With molecular formula C40H45N7O10 and MW 783.84 g/mol, it bridges a high-affinity BRD9 bromodomain ligand (based on 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzyl scaffold) to the thalidomide-derived CRBN E3 ligase recruiter via a triethylene glycol-derived flexible linker. dBRD9 exhibits 10–100-fold enhanced potency over the parent BRD9 inhibitor, achieving DC50 values in the low-nanomolar range (∼10–30 nM) in AML and synovial sarcoma cell lines, and completely depletes BRD9 within 4–6 hours of treatment. It spares closely related bromodomains (BRD2/3/4, BRD7/8) and serves as a key tool for dissecting BAF-complex-dependent transcription, synovial sarcoma oncogenesis, and acute myeloid leukemia (AML) biology.
2. Key Features and Advantages
• Selective BRD9 Degradation: DC50 ∼10–30 nM in MV-4-11 (AML) and SYO-1 (synovial sarcoma) cells; >100-fold selectivity over BRD2/3/4, BRD7/8, and other epigenetic readers.
• CRBN-Recruiting PROTAC Design: Uses thalidomide-warhead (2,6-dioxopiperidin-3-yl-1,3-dioxoisoindolin-4-yl) for cereblon engagement; triethylene glycol linker optimizes ternary complex formation.
• Enhanced vs Parent Inhibitor: 10–100× more potent than the corresponding BRD9 bromodomain ligand alone; drives full BRD9 protein clearance rather than mere competitive blockade.
• Validated In Vivo Activity: Oral or IP dosing (30–100 mg/kg) achieves BRD9 degradation in AML PDX and synovial sarcoma xenografts, suppresses oncogenic gene programs (e.g., MYC, CCND1), and inhibits tumor growth.
• Research-Grade Quality: ≥98% purity (HPLC), light yellow to yellow solid; soluble in DMSO (>10 mg/mL with sonication/warming), suitable for cell-based epigenetics and in vivo pharmacology.
3. Main Applications
• Epigenetics & BAF Complex Research: Studying BRD9 as a non-canonical BAF subunit regulating enhancer–promoter looping, MYC transcription, and chromatin accessibility in AML and solid tumors.
• Synovial Sarcoma & AML Models: dBRD9 is the canonical probe for SS18-SSX fusion-driven synovial sarcoma and AML with high BRD9 dependency; evaluating single-agent degradation vs BRD4 PROTACs (ARV-771/ARV-825).
• PROTAC Technology Development: Reference BRD9 degrader for linker optimization, ternary complex crystallography, and designing next-gen degraders (e.g., dBRD9 analogs, heterobifunctional BRD9–BRD4 dual degraders).
• Drug Combination Studies: Synergy with MRTX1133 (KRAS G12D), SOS1 inhibitors (MRTX0902), venetoclax (BCL2), or IRAK4 blockers (emavusertib) in myeloid malignancies and immunology contexts.
• Mechanistic Degrader vs Inhibitor: Directly comparing dBRD9 (degrader) with parent BRD9 bromodomain inhibitor to demonstrate advantages of protein removal over occupancy-based blockade.
4. Technical Specifications
5. Storage and Handling
Store powder at -20°C in a tightly sealed, desiccated container protected from light; stable for 2–3 years. Prepare DMSO stock at 5–10 mg/mL with sonication and gentle warming to 60 °C (the PEG-linker and isoindoline core dissolve slowly at RT); aliquot to avoid freeze-thaw and store at -80°C up to 6 months or -20°C up to 1 month. For in vivo, formulate in 10% DMSO with 90% saline or corn oil/Tween80 at 1–5 mg/mL; sonicate to clarity. Allow vial to reach room temperature before opening; weigh in fume hood with nitrile gloves and goggles. PROTAC is light-sensitive and contains thalidomide-type motif—handle as potent bioactive/epigenetic degrader.
6. Safety Overview
For laboratory research use only, not for human/veterinary therapeutic or diagnostic use. GHS07 possible (H302 harmful if swallowed, H315/H319 skin/eye irritant). Handle as bioactive PROTAC with epigenetic and teratogenic potential (thalidomide warhead); wear nitrile gloves, goggles, lab coat; avoid dust inhalation, skin contact, and ingestion. Use in fume hood when weighing. Dispose as hazardous organic chemical waste per local regulations. Include DMSO/saline vehicle controls in all cell and animal (AML/SS PDX) assays.
