Name: PROTAC RIPK degrader-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

Purity

99%

Solubility

Soluble in DMSO

Appearance

Solid Powder

Storage

Store at -20°C

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

RGN47169; RGN 47169; RGN-47169; (2S,4R)-1-((S)-17-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-[14-({4-(1,3-Benzothiazol-5-ylamino)-6-[(2-methyl-2-propanyl)sulfonyl]-7-quinolinyl}oxy)-3,6,9,12-tetraoxatetradecan-1-oyl]-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[14-[[4-(5-benzothiazolylamino)-6-[(1,1-dimethylethyl)sulfonyl]-7-quinolinyl]oxy]-1-oxo-3,6,9,12-tetraoxatetradec-1-yl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-; PROTAC_RIPK2

Boiling Point

1196.5±65.0°C at 760 Torr

Density

1.315±0.06 g/cm3 (Predicted)

InChI Key

RIEGJNXDHULIKM-GPPJZCFZSA-N

InChI

InChI=1S/C52H65N7O11S3/c1-33-47(72-31-55-33)35-10-8-34(9-11-35)28-54-49(62)42-25-37(60)29-59(42)50(63)48(51(2,3)4)58-46(61)30-69-21-20-67-17-16-66-18-19-68-22-23-70-43-27-40-38(26-45(43)73(64,65)52(5,6)7)39(14-15-53-40)57-36-12-13-44-41(24-36)56-32-71-44/h8-15,24,26-27,31-32,37,42,48,60H,16-23,25,28-30H2,1-7H3,(H,53,57)(H,54,62)(H,58,61)/t37-,42+,48-/m1/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)COCCOCCOCCOCCOC4=CC5=NC=CC(=C5C=C4S(=O)(=O)C(C)(C)C)NC6=CC7=C(C=C6)SC=N7)O

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-2 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 PROTAC RIPK degrader-2 facilitates the selective degradation of receptor-interacting serine/threonine-protein kinase (RIPK), offering a robust tool for researchers to explore RIPK's role in cell death pathways, inflammation, and disease models. The targeted degradation approach enables precise modulation of RIPK levels, enhancing mechanistic studies in cellular contexts.

• Targeted Protein Degradation in Disease Models: By employing PROTAC RIPK degrader-2, scientists can achieve targeted degradation of RIPK in various disease models. This application is crucial for investigating the therapeutic potential and pathological involvement of RIPK in conditions such as neurodegenerative diseases and inflammatory disorders, providing insights into novel treatment strategies.

• Mechanistic Studies of RIPK Signaling: Utilizing PROTAC RIPK degrader-2 allows researchers to dissect the signaling pathways mediated by RIPK with high specificity. This application supports the elucidation of RIPK's function in cellular signaling networks, contributing to a deeper understanding of its role in apoptosis, necroptosis, and immune responses.

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.

2. Catalytic in vivo protein knockdown by small-molecule PROTACs.

Bondeson, D.P., Mares, A., Smith, I.E., Ko, E., Campos, S., Miah, A.H., Mulholland, K.E., Routly, N., Buckley, D.L., Gustafson, J.L. and Zinn, N., 2015. Nature chemical biology, 11(8), pp.611-617.

The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.

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It is commonly abbreviated as: C₁V₁ = C₂V₂