dBRD9 - CAS 2170679-45-3

dBRD9 is a potent and selective BRD9 bromodomain degrader composed of the BRD9 inhibitor BI 7273 conjugated to the cereblon E3 ligase ligand pomalidomide. dBRD9 has been used in PROTAC technology and exhibits antiproliferative effects in human AML cell lines.

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Molecular Formula
C40H45N7O10
Molecular Weight
783.84

dBRD9

    • Specification
      • Related CAS
        2341840-98-8 (dihydrochloride)
        Purity
        ≥98%
        Solubility
        Soluble in DMSO
        Appearance
        Solid Powder
        Shelf Life
        2 years
        Storage
        Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)
        IUPAC Name
        2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl-methylamino]-N-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethyl]acetamide
        Synonyms
        dBRD-9; dBRD 9; Acetamide, 2-[[[4-(1,2-dihydro-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]methylamino]-N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethyl]-; 2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide
    • Properties
      • Boiling Point
        1014.2±65.0°C at 760 Torr
        Density
        1.357±0.06 g/cm3
        InChI Key
        AIOCFZJGGGEWDK-UHFFFAOYSA-N
        InChI
        InChI=1S/C40H45N7O10/c1-45(21-29-32(54-3)18-24(19-33(29)55-4)28-22-46(2)38(51)27-20-41-11-10-25(27)28)23-35(49)43-13-15-57-17-16-56-14-12-42-30-7-5-6-26-36(30)40(53)47(39(26)52)31-8-9-34(48)44-37(31)50/h5-7,10-11,18-20,22,31,42H,8-9,12-17,21,23H2,1-4H3,(H,43,49)(H,44,48,50)
        Canonical SMILES
        CN1C=C(C2=C(C1=O)C=NC=C2)C3=CC(=C(C(=C3)OC)CN(C)CC(=O)NCCOCCOCCNC4=CC=CC5=C4C(=O)N(C5=O)C6CCC(=O)NC6=O)OC
    • Reference Reading
      • 1. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands.
        Remillard, D., Buckley, D.L., Paulk, J., Brien, G.L., Sonnett, M., Seo, H.S., Dastjerdi, S., Wühr, M., Dhe-Paganon, S., Armstrong, S.A. and Bradner, J.E., 2017. Angewandte Chemie International Edition, 56(21), pp.5738-5743.
        The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10- to 100-fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.
        2. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel-Lindau (VHL) based dual degrader probe of BRD9 and BRD7.
        Zoppi, V., Hughes, S.J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K.M., Daniels, D.L., Spallarossa, A. and Ciulli, A., 2018. Journal of medicinal chemistry, 62(2), pp.699-726.
        Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations.
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