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

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IUPACName

(4S,7S,9aS)-N-[(1R)-6-[4-[4-[(3R)-3-[4-[[4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]benzoyl]sulfamoyl]-2-(trifluoromethylsulfonyl)anilino]-4-phenylsulfanylbutyl]piperazin-1-yl]-4-oxobutoxy]-1,2,3,4-tetrahydronaphthalen-1-yl]-8,8-dimethyl-4-[[(2S)-2-(methylamino)propanoyl]amino]-5-oxo-2,3,4,7,9,9a-hexahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

Synonyms

Pyrrolo[2,1-b][1,3]oxazepine-7-carboxamide, N-[(1R)-6-[4-[4-[(3R)-3-[[4-[[[4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]benzoyl]amino]sulfonyl]-2-[(trifluoromethyl)sulfonyl]phenyl]amino]-4-(phenylthio)butyl]-1-piperazinyl]-4-oxobutoxy]-1,2,3,4-tetrahydro-1-naphthalenyl]octahydro-8,8-dimethyl-4-[[(2S)-2-(methylamino)-1-oxopropyl]amino]-5-oxo-, (4S,7S,9aS)-; (4S,7S,9aS)-N-((R)-6-(4-(4-((R)-3-((4-(N-(4-(4-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-4-oxobutoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide; (4S,7S,9aS)-N-[(1R)-6-(4-{4-[(3R)-3-[(4-{[4-(4-{[2-(4-Chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)benzoyl]sulfamoyl}-2-[(trifluoromethyl)sulfonyl]phenyl)amino]-4-(phenylsulfanyl)butyl]-1-piperazinyl}-4-oxobutoxy)-1,2,3,4-tetrahydro-1-naphthalenyl]-8,8-dimethyl-4-[(N-methyl-L-alanyl)amino]-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxamide

Density

1.39±0.1 g/cm3

InChI Key

HHMCHRRZMCHLLA-PYINPHMPSA-N

InChI

InChI=1S/C76H96ClF3N10O11S3/c1-50(81-6)70(92)84-65-31-43-101-68-47-75(4,5)69(90(68)73(65)95)72(94)83-63-15-10-12-53-44-58(25-27-62(53)63)100-42-11-16-67(91)89-40-34-86(35-41-89)33-30-56(49-102-59-13-8-7-9-14-59)82-64-28-26-60(45-66(64)103(96,97)76(78,79)80)104(98,99)85-71(93)52-19-23-57(24-20-52)88-38-36-87(37-39-88)48-54-46-74(2,3)32-29-61(54)51-17-21-55(77)22-18-51/h7-9,13-14,17-28,44-45,50,56,63,65,68-69,81-82H,10-12,15-16,29-43,46-49H2,1-6H3,(H,83,94)(H,84,92)(H,85,93)/t50-,56+,63+,65-,68-,69+/m0/s1

SMILES

CC(C(=O)NC1CCOC2CC(C(N2C1=O)C(=O)NC3CCCC4=C3C=CC(=C4)OCCCC(=O)N5CCN(CC5)CCC(CSC6=CC=CC=C6)NC7=C(C=C(C=C7)S(=O)(=O)NC(=O)C8=CC=C(C=C8)N9CCN(CC9)CC1=C(CCC(C1)(C)C)C1=CC=C(C=C1)Cl)S(=O)(=O)C(F)(F)F)(C)C)NC

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-1 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 application focuses on utilizing PROTAC Bcl-xL degrader-1 to selectively degrade the Bcl-xL protein. By targeting this anti-apoptotic protein, researchers can explore mechanisms of apoptosis and investigate potential therapeutic strategies for diseases characterized by dysregulated cell death pathways.

• Cancer Research: Targeted Degradation: Employing PROTAC Bcl-xL degrader-1 allows researchers to study the role of Bcl-xL in cancer cell survival. This targeted degradation approach provides insights into the dependency of cancer cells on Bcl-xL, facilitating the development of novel cancer treatment strategies that exploit vulnerabilities in apoptotic regulation.

• Apoptosis Pathway Exploration: Researchers can use PROTAC Bcl-xL degrader-1 to dissect the molecular interactions within the apoptosis pathway. By degrading Bcl-xL, this tool aids in understanding how Bcl-xL interacts with other proteins to regulate cell survival, offering a deeper understanding of apoptotic signaling cascades.

• Drug Resistance Studies: Targeted Protein Degradation: Investigating drug resistance mechanisms becomes feasible with PROTAC Bcl-xL degrader-1. It enables the targeted degradation of Bcl-xL in resistant cell lines, helping to unravel resistance pathways and identify combination therapies that could overcome Bcl-xL mediated drug resistance.

1. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines.

Zhang, X., He, Y., Zhang, P., Budamagunta, V., Lv, D., Thummuri, D., Yang, Y., Pei, J., Yuan, Y., Zhou, D. and Zheng, G., 2020. European journal of medicinal chemistry, 199, p.112397.

Targeting BCL-XL via PROTACs is a promising strategy in reducing BCL-XL inhibition associated platelet toxicity. Recently, we reported potent BCL-XL PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-XL degradation. Among those PROTACs, compound 8a efficiently degrades BCL-XL in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-XL degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.

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It is commonly abbreviated as: C₁V₁ = C₂V₂