Name: RC32
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Powder

Storage

Store at -20°C

IUPACName

(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-12-[(2R)-1-[(1S,3R,4R)-4-[2-[[1-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethyl]triazol-4-yl]methoxy]ethoxy]-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^4,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

Synonyms

FKBP12 PROTAC RC32; Rapamycin, 42-O-[2-[[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethyl]-1H-1,2,3-triazol-4-yl]methoxy]ethyl]-; 42-O-[2-[[1-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethyl]-1H-1,2,3-triazol-4-yl]methoxy]ethyl]rapamycin

Density

1.31±0.1 g/cm3

InChI Key

XCSUEITWRRFFMN-XLXRSZBYSA-N

InChI

InChI=1S/C75H107N7O20/c1-45-17-12-11-13-18-46(2)61(94-8)41-54-24-22-51(7)75(93,102-54)69(87)73(91)81-29-15-14-21-58(81)74(92)101-62(42-59(83)47(3)38-50(6)67(86)68(96-10)66(85)49(5)37-45)48(4)39-52-23-26-60(63(40-52)95-9)100-36-35-99-44-53-43-80(79-78-53)30-32-98-34-33-97-31-28-76-56-20-16-19-55-65(56)72(90)82(71(55)89)57-25-27-64(84)77-70(57)88/h11-13,16-20,38,43,45,47-49,51-52,54,57-58,60-63,67-68,76,86,93H,14-15,21-37,39-42,44H2,1-10H3,(H,77,84,88)/b13-11+,17-12-,46-18+,50-38-/t45-,47-,48-,49-,51-,52+,54+,57?,58+,60-,61+,62+,63-,67-,68+,75-/m1/s1

SMILES

O=C1OC(CC(=O)C(C=C(C)C(O)C(OC)C(=O)C(C)CC(C=CC=CC=C(C)C(OC)CC2OC(O)(C(=O)C(=O)N3CCCCC13)C(C)CC2)C)C)C(C)CC4CCC(OCCOCC=5N=NN(C5)CCOCCOCCNC6=CC=CC=7C(=O)N(C(=O)C67)C8C(=O)NC(=O)CC8)C(OC)C4

Mechanism

Target: RC32 selectively targets FKBP12, the twelve-kilodalton FK506-binding immunophilin protein.

Binding site: Its FKBP12 ligand occupies the canonical FK506-binding hydrophobic pocket.

Mechanism of action: RC32 is a FKBP12-directed PROTAC that induces potent and selective degradation of FKBP12. It combines an FKBP12-recognition ligand with an E3 ligase-recruiting element, allowing FKBP12 to be brought into proximity with ubiquitination machinery and subsequently degraded by the proteasome. This mechanism enables functional studies of FKBP12 depletion without relying solely on ligand occupancy or immunophilin inhibition. RC32 is particularly useful for examining FKBP12-dependent regulation of BMP-SMAD signaling, hepcidin expression, protein turnover kinetics, and the cellular consequences of removing FKBP12 from signaling complexes.

Applications

• Targeted Degradation of Oncogenic Proteins: RC32 is utilized in the selective degradation of oncogenic proteins, offering a promising approach for cancer research. By leveraging the PROTAC mechanism, RC32 facilitates the recruitment of E3 ubiquitin ligases to target proteins, promoting their ubiquitination and subsequent proteasomal degradation.

• PROTAC-Mediated Kinase Inhibition: RC32 serves as a pivotal tool in studying kinase regulation by enabling the targeted degradation of specific kinases. This application allows researchers to dissect kinase-dependent signaling pathways and understand their roles in cellular processes, providing insights into potential therapeutic targets.

• Investigation of Protein Homeostasis: RC32 is instrumental in exploring the dynamics of protein homeostasis through targeted protein degradation. By degrading specific proteins, researchers can study the effects on cellular proteostasis, offering a deeper understanding of diseases related to protein misfolding and aggregation.

• Studying E3 Ligase Specificity: RC32 aids in examining the specificity of E3 ubiquitin ligases within the PROTAC framework. This application enables the identification of ligase-substrate interactions, contributing to the design of more efficient and selective PROTACs for targeted protein degradation research.

1. A chemical approach for global protein knockdown from mice to non-human primates.

Sun, X., Wang, J., Yao, X., Zheng, W., Mao, Y., Lan, T., Wang, L., Sun, Y., Zhang, X., Zhao, Q. and Zhao, J., 2019. Cell Discovery, 5(1), pp.1-13.

Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.

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