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PROTAC Bcl-xL degrader-2

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PROTAC Bcl-xL degrader-2 is a potent Bcl-xL (Bcl-2 family member) degrader based on von Hippel-Lindau ligand, with an IC50 of 0.6 nM.

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Molecular Formula

C68H80N8O14S3

Molecular Weight

1329.60

PROTAC Bcl-xL degrader-2

- Specification
  - IUPAC Name
    
    2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[2-[2-[2-[3-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-ynyl]phenoxy]propyl]-1,3-thiazole-4-carboxylic acid
    
    Synonyms
    
    2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-(4-((S)-24-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-25,25-dimethyl-22-oxo-4,7,10,13,16,19-hexaoxa-23-azahexacos-1-yn-1-yl)phenoxy)propyl)thiazole-4-carboxylic acid; N-{22-[4-(3-{2-[8-(1,3-Benzothiazol-2-ylcarbamoyl)-3,4-dihydro-2(1H)-isoquinolinyl]-4-carboxy-1,3-thiazol-5-yl}propoxy)phenyl]-4,7,10,13,16,19-hexaoxadocos-21-ynoyl}-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[22-[4-[3-[2-[8-[(2-benzothiazolylamino)carbonyl]-3,4-dihydro-2(1H)-isoquinolinyl]-4-carboxy-5-thiazolyl]propoxy]phenyl]-1-oxo-4,7,10,13,16,19-hexaoxadocos-21-yn-1-yl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-
- Properties
  - Density
    
    1.4±0.1 g/cm3
    
    InChI Key
    
    LOJJAKUNUJJOKC-MXEISZGISA-N
    
    InChI
    
    InChI=1S/C68H80N8O14S3/c1-45-60(91-44-70-45)49-20-16-47(17-21-49)41-69-63(80)55-40-50(77)42-76(55)64(81)61(68(2,3)4)72-58(78)25-29-85-31-33-87-35-37-89-39-38-88-36-34-86-32-30-84-27-8-10-46-18-22-51(23-19-46)90-28-9-15-57-59(65(82)83)73-67(93-57)75-26-24-48-11-7-12-52(53(48)43-75)62(79)74-66-71-54-13-5-6-14-56(54)92-66/h5-7,11-14,16-23,44,50,55,61,77H,9,15,24-43H2,1-4H3,(H,69,80)(H,72,78)(H,82,83)(H,71,74,79)/t50-,55+,61-/m1/s1
    
    Canonical SMILES
    
    CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CCOCCOCCOCCOCCOCCOCC#CC4=CC=C(C=C4)OCCCC5=C(N=C(S5)N6CCC7=C(C6)C(=CC=C7)C(=O)NC8=NC9=CC=CC=C9S8)C(=O)O)O
- Reference Reading
  - 1. Structural insights into PROTAC-mediated degradation of Bcl-xL.
    
    Chung, C.W., Dai, H., Fernandez, E., Tinworth, C.P., Churcher, I., Cryan, J., Denyer, J., Harling, J.D., Konopacka, A., Queisser, M.A. and Tame, C.J., 2020. ACS Chemical Biology, 15(9), pp.2316-2323.
    
    The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, Proteolysis Targeting Chimeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.

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Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳

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