Name: PROTAC Bcl-xL degrader-3
Brand: BOC Sciences
Rating: 5 (1 reviews)

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IUPACName

(2S,4R)-1-[(2S)-2-[[8-[4-[[(1R)-4-(4-chlorophenyl)-1-methyl-3-[[4-[4-[[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylcarbamoyl]phenyl]piperazin-1-yl]methyl]cyclohex-3-en-1-yl]methyl]piperazin-1-yl]-8-oxooctanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Synonyms

753b; (2S,4R)-1-((S)-2-(8-(4-(((R)-4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Density

1.39±0.1 g/cm3

InChI Key

KQEMZZJSHJCPSI-RYFXIQSLSA-N

InChI

InChI=1S/C82H105ClF3N11O11S4/c1-56(58-18-20-60(21-19-58)75-57(2)87-55-110-75)88-78(102)71-48-66(98)52-97(71)79(103)76(80(3,4)5)90-73(99)16-12-7-8-13-17-74(100)96-42-38-94(39-43-96)54-81(6)34-32-69(59-22-26-63(83)27-23-59)62(50-81)51-93-36-40-95(41-37-93)65-28-24-61(25-29-65)77(101)91-112(106,107)68-30-31-70(72(49-68)111(104,105)82(84,85)86)89-64(33-35-92-44-46-108-47-45-92)53-109-67-14-10-9-11-15-67/h9-11,14-15,18-31,49,55-56,64,66,71,76,89,98H,7-8,12-13,16-17,32-48,50-54H2,1-6H3,(H,88,102)(H,90,99)(H,91,101)/t56-,64+,66+,71-,76+,81+/m0/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)C(C)NC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CCCCCCC(=O)N4CCN(CC4)CC5(CCC(=C(C5)CN6CCN(CC6)C7=CC=C(C=C7)C(=O)NS(=O)(=O)C8=CC(=C(C=C8)NC(CCN9CCOCC9)CSC1=CC=CC=C1)S(=O)(=O)C(F)(F)F)C1=CC=C(C=C1)Cl)C)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-3 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 the PROTAC Bcl-xL degrader-3 to selectively degrade the Bcl-xL protein, a key regulator of apoptosis. By targeting Bcl-xL, researchers can explore mechanisms of cell survival and apoptotic pathways, providing insights into cancer biology and potential therapeutic strategies.

• Targeted Protein Degradation in Cancer Research: PROTAC Bcl-xL degrader-3 serves as a valuable tool for investigating the role of Bcl-xL in tumorigenesis. Its ability to induce targeted degradation of Bcl-xL allows for the study of cancer cell dependency on anti-apoptotic proteins, potentially identifying novel targets for cancer treatment.

• Mechanistic Studies of Apoptosis: Employing PROTAC Bcl-xL degrader-3 enables detailed analysis of apoptotic processes by selectively degrading Bcl-xL. This approach aids in dissecting the molecular interactions and pathways involved in programmed cell death, offering a deeper understanding of apoptosis regulation in various cellular contexts.

• Drug Resistance Investigation: The use of PROTAC Bcl-xL degrader-3 in research settings can help elucidate the mechanisms underlying drug resistance in cancer cells. By degrading Bcl-xL, researchers can assess the impact on cell survival and resistance pathways, contributing to the development of more effective therapeutic interventions.

1. Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity.

Lv, D., Pal, P., Liu, X., Jia, Y., Thummuri, D., Zhang, P., Hu, W., Pei, J., Zhang, Q., Zhou, S. and Khan, S., 2021. Nature communications, 12(1), pp.1-14.

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.

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It is commonly abbreviated as: C₁V₁ = C₂V₂