Name: RIPK2-IN-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

IUPACName

(2S)-N-[(1S)-1-[1-[2-[4-[2-[6-tert-butylsulfonyl-4-[(4,5-dimethyl-1H-pyrazol-3-yl)amino]quinazolin-7-yl]oxyethyl]piperazin-1-yl]pyrimidine-5-carbonyl]piperidin-4-yl]-2-[(2S)-2-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide

Synonyms

(S)-N-((S)-1-(1-(2-(4-(2-((6-(tert-Butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)piperidin-4-yl)-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide

Density

1.353±0.06 g/cm3

InChI Key

HZMQXNZSFFXKMT-LCPJFFRWSA-N

InChI

InChI=1S/C53H65FN14O7S2/c1-31-32(2)63-64-46(31)62-47-38-25-43(77(73,74)53(4,5)6)42(26-39(38)58-30-59-47)75-24-23-65-19-21-67(22-20-65)52-56-27-36(28-57-52)50(71)66-17-14-34(15-18-66)44(61-48(70)33(3)55-7)51(72)68-16-8-9-41(68)49-60-40(29-76-49)45(69)35-10-12-37(54)13-11-35/h10-13,25-30,33-34,41,44,55H,8-9,14-24H2,1-7H3,(H,61,70)(H2,58,59,62,63,64)/t33-,41-,44-/m0/s1

SMILES

O=C(C=1N=C(SC1)C2N(C(=O)C(NC(=O)C(NC)C)C3CCN(C(=O)C4=CN=C(N=C4)N5CCN(CCOC6=CC7=NC=NC(NC8=NNC(=C8C)C)=C7C=C6S(=O)(=O)C(C)(C)C)CC5)CC3)CCC2)C9=CC=C(F)C=C9

Mechanism

Target: RIPK2-IN-2 selectively targets receptor-interacting serine/threonine-protein kinase 2.

Binding site: Its RIPK2 ligand binds the ATP-competitive catalytic pocket of RIPK2.

Mechanism of action: RIPK2-IN-2 is a VHL-recruiting RIPK2 PROTAC inhibitor designed to suppress RIPK2-dependent inflammatory signaling through targeted degradation. The molecule simultaneously binds RIPK2 and VHL, enabling formation of a ternary complex that promotes RIPK2 ubiquitination and proteasomal depletion. This degradation-based mechanism can reduce RIPK2 kinase-dependent and scaffold-associated signaling outputs downstream of NOD2 pathway activation. In research applications, RIPK2-IN-2 supports studies of innate immune signaling, proinflammatory cytokine regulation, degradation kinetics, kinase selectivity, and the difference between catalytic inhibition and complete RIPK2 protein removal.

Applications

• PROTAC-Mediated RIPK2 Degradation: RIPK2-IN-2 is utilized in research to selectively degrade RIPK2, a kinase involved in inflammatory signaling pathways. This application aids in dissecting RIPK2's role in immune responses, offering insights into potential therapeutic targets for inflammatory diseases.

• Targeted Degradation in Signal Transduction: By employing RIPK2-IN-2, researchers can explore the intricate mechanisms of signal transduction pathways. This PROTAC approach allows for precise modulation of protein levels, facilitating studies on the dynamic regulation of signaling networks.

• Investigating Protein-Protein Interactions: The application of RIPK2-IN-2 in targeted protein degradation experiments helps elucidate the interactions between RIPK2 and other signaling molecules. This method provides a powerful tool for mapping protein interaction networks and understanding their biological implications.

• Functional Genomics via PROTACs: RIPK2-IN-2 serves as a critical tool in functional genomics, enabling the study of gene function through targeted protein degradation. Researchers can employ this strategy to investigate the consequences of RIPK2 depletion on cellular phenotypes and biological processes.

1. Optimization of a Series of RIPK2 PROTACs.

Miah, A.H., Smith, I.E., Rackham, M., Mares, A., Thawani, A.R., Nagilla, R., Haile, P.A., Votta, B.J., Gordon, L.J., Watt, G. and Denyer, J., 2021. Journal of Medicinal Chemistry, 64(17), pp.12978-13003.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

2. 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.

Stock concentration: *

Desired final volume: *

Desired concentration: *

* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂