Name: PROTAC RIPK degrader-6
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Store at -20°C

IUPACName

2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]acetamide

Synonyms

Acetamide, 2-[2-[2-[2-[2-[[4-(5-benzothiazolylamino)-6-[(1,1-dimethylethyl)sulfonyl]-7-quinolinyl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]-N-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-4-yl]-; 14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecanamide

Boiling Point

1111.1±65.0°C at 760 Torr

Density

1.398±0.06 g/cm3

InChI Key

BRZGXSNAXRPPFI-UHFFFAOYSA-N

InChI

InChI=1S/C43H48N6O11S2/c1-43(2,3)62(54,55)38-22-29-32(46-27-7-9-37-34(21-27)45-26-61-37)11-12-44-33(29)23-36(38)60-20-19-58-16-15-56-13-14-57-17-18-59-25-40(51)47-31-6-4-5-28-30(31)24-49(42(28)53)35-8-10-39(50)48-41(35)52/h4-7,9,11-12,21-23,26,35H,8,10,13-20,24-25H2,1-3H3,(H,44,46)(H,47,51)(H,48,50,52)

SMILES

CC(C)(C)S(=O)(=O)C1=CC2=C(C=CN=C2C=C1OCCOCCOCCOCCOCC(=O)NC3=CC=CC4=C3CN(C4=O)C5CCC(=O)NC5=O)NC6=CC7=C(C=C6)SC=N7

Mechanism

Target: Targets RIPK family kinase proteins for experimental targeted protein degradation studies.

Binding Site: Binds the RIPK kinase ATP-binding pocket and linked E3 ligase recruitment element to support productive ternary complex formation.

Mechanism of Action: PROTAC RIPK degrader-6 is designed for use in PROTAC or targeted protein degradation experiments directed toward RIPK family kinase proteins. The bifunctional molecule links a target-recognition element to cereblon, 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 RIPK Degradation: This compound facilitates the targeted degradation of receptor-interacting protein kinases (RIPKs), offering a powerful tool for studying the role of these kinases in necroptosis and inflammation. By selectively degrading RIPKs, researchers can dissect complex signaling pathways and explore potential therapeutic interventions for inflammatory diseases.

• Targeted Protein Degradation in Cell Death Pathways: PROTAC RIPK degrader-6 enables the precise removal of RIPKs, crucial mediators in programmed cell death. This application aids in elucidating the mechanistic underpinnings of necroptosis, providing insights into cellular responses to stress and injury, and advancing the understanding of cell fate decisions.

• Investigating RIPK-Related Signal Transduction: By employing PROTAC technology, this degrader allows for the selective depletion of RIPKs, essential components in various signal transduction pathways. Researchers can utilize this tool to examine the downstream effects of RIPK loss, facilitating the discovery of novel regulatory nodes within these signaling networks.

• Exploring Therapeutic Targets in Inflammatory Disorders: The application of PROTAC RIPK degrader-6 in research settings provides a strategic approach for identifying and validating new therapeutic targets. By degrading RIPKs, this product supports the investigation of their contributions to inflammation and immune responses, paving the way for novel anti-inflammatory strategies.

1. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Mares, A., Miah, A.H., Smith, I.E., Rackham, M., Thawani, A.R., Cryan, J., Haile, P.A., Votta, B.J., Beal, A.M., Capriotti, C. and Reilly, M.A., 2020. Communications biology, 3(1), pp.1-13.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

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It is commonly abbreviated as: C₁V₁ = C₂V₂