Name: Sarm-Nutlin Protac
Brand: BOC Sciences
Rating: 5 (1 reviews)

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$--

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ShelfLife

2 years

IUPACName

(2S)-3-[4-[[2-[2-[2-[2-[[2-[4-[(4R,5S)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-2-oxopiperazin-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]phenoxy]-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide

Synonyms

(S)-3-(4-(1-(4-((4R,5S)-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazin-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-amido)phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide; 14-(4-{[(4R,5S)-4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazol-1-yl]carbonyl}-2-oxo-1-piperazinyl)-N-{4-[(2S)-2-hydroxy-2-methyl-3-{[4-nitro-3-(trifluoromethyl)phenyl]amino}-3-oxopropoxy]phenyl}-13-oxo-3,6,9-trioxa-12-azatetradecan-1-amide; 1-Piperazineacetamide, 4-[[(4R,5S)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-N-[2-[2-[2-[2-[[4-[(2S)-2-hydroxy-2-methyl-3-[[4-nitro-3-(trifluoromethyl)phenyl]amino]-3-oxopropoxy]phenyl]amino]-2-oxoethoxy]ethoxy]ethoxy]ethyl]-2-oxo-

Density

1.40±0.1 g/cm3

InChI Key

VKTBFTIPDGAIPC-BIOIQHPWSA-N

InChI

InChI=1S/C57H61Cl2F3N8O14/c1-35(2)84-47-30-43(79-4)18-19-44(47)53-66-51(36-5-9-38(58)10-6-36)52(37-7-11-39(59)12-8-37)69(53)55(75)68-23-22-67(50(73)32-68)31-48(71)63-21-24-80-25-26-81-27-28-82-33-49(72)64-40-13-16-42(17-14-40)83-34-56(3,76)54(74)65-41-15-20-46(70(77)78)45(29-41)57(60,61)62/h5-20,29-30,35,51-52,76H,21-28,31-34H2,1-4H3,(H,63,71)(H,64,72)(H,65,74)/t51-,52+,56+/m1/s1

SMILES

CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCN(C(=O)C3)CC(=O)NCCOCCOCCOCC(=O)NC4=CC=C(C=C4)OCC(C)(C(=O)NC5=CC(=C(C=C5)[N+](=O)[O-])C(F)(F)F)O)C6=CC=C(C=C6)Cl)C7=CC=C(C=C7)Cl

Mechanism

Target: Sarm-Nutlin Protac targets androgen receptor through a selective androgen receptor modulator.

Binding site: Its SARM moiety binds the androgen receptor ligand-binding domain.

Mechanism of action: Sarm-Nutlin Protac is an early all-small-molecule PROTAC designed to degrade androgen receptor by recruiting the MDM2 E3 ubiquitin ligase. The molecule links a nonsteroidal SARM-derived androgen receptor ligand to nutlin, an MDM2-binding ligand, through a PEG-based linker. Simultaneous engagement of androgen receptor and MDM2 promotes target ubiquitination and proteasome-dependent degradation. This compound is useful as a foundational research tool for studying chemically induced proximity, MDM2-recruited degradation, androgen receptor turnover, and the mechanistic distinction between receptor antagonism and targeted receptor depletion.

Applications

• PROTAC-Mediated MDM2 Degradation: Sarm-Nutlin Protac facilitates the targeted degradation of MDM2, a critical negative regulator of the p53 tumor suppressor. By promoting the proteasomal degradation of MDM2, this PROTAC enhances p53 activity, offering a valuable tool for studying p53-dependent cellular processes and cancer biology.

• Targeted Protein Degradation in Cancer Research: Utilizing Sarm-Nutlin Protac enables researchers to selectively degrade oncogenic proteins, providing insights into tumorigenesis mechanisms. This PROTAC serves as a powerful experimental approach for dissecting the roles of specific proteins in cancer cell proliferation and survival.

• E3 Ligase Recruitment Efficiency: Sarm-Nutlin Protac is designed to efficiently recruit E3 ligases to its target protein, facilitating ubiquitination and subsequent degradation. This capability is crucial for researchers developing novel strategies for targeted protein degradation and understanding the dynamics of protein turnover in cells.

• Investigating Protein-Protein Interactions: The application of Sarm-Nutlin Protac allows for the exploration of protein-protein interactions by selectively degrading one interaction partner. This approach aids in elucidating complex signaling pathways and the functional consequences of disrupting specific protein complexes.

1. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.

Schneekloth, A.R., Pucheault, M., Tae, H.S. and Crews, C.M., 2008. Bioorganic & medicinal chemistry letters, 18(22), pp.5904-5908.

We have developed a heterobifunctional all-small molecule PROTAC (PROteolysis TArgeting Chimera) capable of inducing proteasomal degradation of the androgen receptor. This cell permeable PROTAC consists of a non-steroidal androgen receptor ligand (SARM) and the MDM2 ligand known as nutlin, connected by a PEG-based linker. The SARM-nutlin PROTAC recruits the androgen receptor to MDM2, which functions as an E3 ubiquitin ligase. This leads to the ubiquitination of the androgen receptor, and its subsequent degradation by the proteasome. Upon treatment of HeLa cells with 10 μM PROTAC for 7 h, we were able to observe a decrease in androgen receptor levels. This degradation is proteasome dependent, as it is mitigated in cells pre-treated with 10 μM epoxomicin, a specific proteasome inhibitor. These results have implications for the potential study and treatment of various cancers with increased androgen receptor levels.

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