PROTAC BRD2/BRD4 degrader-1 - CAS 2570470-42-5

Inquiry

PROTAC BRD2/BRD4 degrader-1 is a potent and selective degrader of BET proteins BRD4 and BRD2, linking Cereblon and BET via ligands. It rapidly induces reversible, long-lasting and unexpectedly selective removal of BRD4 and BRD2 over BRD3. It effectively inhibits solid tumors with low cytotoxic effect, and is composed of BET inhibitor, a linker, and the ligand thalidomide for cereblon (CRBN)/cullin 4A.

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Molecular Formula

C39H38N6O9S

Molecular Weight

766.82

PROTAC BRD2/BRD4 degrader-1

- Specification
  - Solubility
    
    Soluble in DMSO
    
    IUPAC Name
    
    N-[4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]butyl]-3-[6-[(2-methoxyphenyl)sulfonylamino]-1-methyl-2-oxobenzo[cd]indol-4-yl]propanamide
    
    Synonyms
    
    NSC-812346; N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-3-(6-((2-methoxyphenyl)sulfonamido)-1-methyl-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)propanamide; Benz[cd]indole-4-propanamide, N-[4-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]butyl]-1,2-dihydro-6-[[(2-methoxyphenyl)sulfonyl]amino]-1-methyl-2-oxo-; N-[4-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]butyl]-1,2-dihydro-6-[[(2-methoxyphenyl)sulfonyl]amino]-1-methyl-2-oxobenz[cd]indole-4-propanamide
- Properties
  - Density
    
    1.466±0.06 g/cm3
    
    InChI Key
    
    DCPKSVYPNGBDSB-UHFFFAOYSA-N
    
    InChI
    
    InChI=1S/C39H38N6O9S/c1-44-28-14-13-26(43-55(52,53)31-11-4-3-10-30(31)54-2)24-20-22(21-25(34(24)28)37(44)49)12-16-32(46)41-19-6-5-18-40-27-9-7-8-23-35(27)39(51)45(38(23)50)29-15-17-33(47)42-36(29)48/h3-4,7-11,13-14,20-21,29,40,43H,5-6,12,15-19H2,1-2H3,(H,41,46)(H,42,47,48)
    
    Canonical SMILES
    
    CN1C2=C3C(=CC(=CC3=C(C=C2)NS(=O)(=O)C4=CC=CC=C4OC)CCC(=O)NCCCCNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O)C1=O
- Reference Reading
  - 1. Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies.
    
    Jiang, F., Wei, Q., Li, H., Li, H., Cui, Y., Ma, Y., Chen, H., Cao, P., Lu, T. and Chen, Y., 2020. Bioorganic & Medicinal Chemistry, 28(1), p.115181.
    
    The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.

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