Name: PROTAC Bcl-xL degrader-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

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IUPACName

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)-

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

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

Mechanism

Target: Targets BCL-XL and related anti-apoptotic BCL-2 family proteins for experimental targeted protein degradation studies.

Binding Site: Binds the BCL-family BH3-binding groove and recruited E3 ligase ligand site to support productive ternary complex formation.

Mechanism of Action: PROTAC Bcl-xL degrader-2 is designed for use in PROTAC or targeted protein degradation experiments directed toward BCL-XL and related anti-apoptotic BCL-2 family proteins. The bifunctional molecule links a target-recognition element to VHL, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated Bcl-xL Degradation: This product facilitates the targeted degradation of Bcl-xL, a critical anti-apoptotic protein, using the PROTAC technology. Researchers can leverage this degrader to study Bcl-xL's role in apoptosis regulation and cancer cell survival, thereby advancing the understanding of therapeutic strategies for cancer treatment.

• Apoptosis Pathway Investigation: Employing PROTAC Bcl-xL degrader-2 allows for the precise modulation of apoptosis pathways by degrading Bcl-xL. This application is crucial for dissecting the molecular mechanisms of cell death and survival, offering insights into the design of novel anti-cancer therapies.

• Cancer Biology Research: With its ability to selectively degrade Bcl-xL, this PROTAC tool is invaluable for exploring the contribution of Bcl-xL in tumorigenesis. Researchers can utilize this degrader to interrogate cancer cell dependencies and identify potential vulnerabilities in cancer cells.

• Drug Resistance Studies: By targeting Bcl-xL for degradation, this product aids in the investigation of drug resistance mechanisms in cancer cells. Understanding how Bcl-xL degradation affects resistance pathways can inform the development of more effective combinatorial treatment strategies.

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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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂