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| Targets |
RS2 targets PDK1 (3-phosphoinositide-dependent protein kinase 1), a master kinase that plays a central role in the PI3K/AKT signaling pathway. PDK1 phosphorylates and activates a subset of AGC kinases, including AKT, S6K, SGK, and PKC isoforms. RS2 is a substrate-selective PDK1 inhibitor that functions as a bioactive mimetic of the PIFtide peptide docking motif. It binds to the PIF-pocket of PDK1 with a Kd of 9 µM. By binding to this allosteric site, RS2 selectively inhibits the activation of downstream kinases that depend on PIF-pocket docking, such as S6K1, without blocking the activation of other PDK1 substrates like PKB/Akt. This substrate-selective inhibition makes RS2 a unique tool for dissecting PDK1 signaling pathways.
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| ln Vitro |
The catalytic activity of PDK1 on peptide substrates is six times increased by PDK1-IN-RS2. PDK1-IN-RS2's sulfonyl group interacts with Arg131 via a salt bridge because crystallization circumstances may induce the sulfonamide to ionize [1].
In vitro studies have characterized RS2 as a substrate-selective inhibitor of PDK1. It exhibits a binding affinity (Kd) of 9 µM for PDK1. RS2 suppresses the activation of downstream kinase S6K1 by PDK1. The catalytic activity of PDK1 on peptide substrates is increased six-fold by RS2. The compound's sulfonyl group interacts with Arg131 via a salt bridge. RS2 is a PIFtide mimetic and serves as a useful comparator to the activator PS210. A co-crystal structure of RS2 with PDK1 is available (PDB: 4RQV, 1.50 Å) for computational design. These findings confirm that RS2 is a unique substrate-selective inhibitor of PDK1. |
| ln Vivo |
In vivo activity data for RS2 is limited, as the compound is primarily used as a research tool in in vitro studies. However, its mechanism of action—substrate-selective inhibition of PDK1—suggests potential in vivo applications in studying PDK1 signaling pathways and their role in diseases such as cancer and metabolic disorders. RS2's selectivity for inhibiting S6K1 activation without blocking AKT activation makes it a valuable tool for dissecting the distinct roles of PDK1 substrates in vivo. However, specific in vivo protocols and results, such as dosing regimens, routes of administration, and pharmacokinetic parameters, are not detailed in the available literature.
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| Enzyme Assay |
The in vitro assays for RS2 measure its binding to PDK1 and its effects on PDK1 substrate activation. Binding affinity is typically measured using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). RS2 exhibits a Kd of 9 µM for PDK1. To assess substrate selectivity, the compound's effects on the activation of various PDK1 substrates, such as S6K1 and AKT, are measured. In kinase assays, PDK1 is incubated with its substrates (e.g., S6K1 or AKT) and ATP in the presence of varying concentrations of RS2. The phosphorylation of the substrates is measured, and the inhibition of activation is assessed. RS2 selectively inhibits the activation of S6K1 without affecting AKT activation. These assays confirm the substrate-selective inhibition of RS2.
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| Cell Assay |
In vitro cell-based assays for RS2 are used to study its effects on PDK1-mediated signaling in cells. A common assay involves treating cells with RS2 and measuring the phosphorylation of PDK1 substrates. Cells are lysed, and the levels of phosphorylated S6K1, AKT, and other downstream targets are assessed by Western blotting using phospho-specific antibodies. RS2 selectively inhibits S6K1 phosphorylation without affecting AKT phosphorylation. Cell proliferation or viability assays can also be performed to assess the functional consequences of PDK1 inhibition. These cell-based assays confirm that RS2 is a substrate-selective inhibitor of PDK1 in a cellular context.
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| Animal Protocol |
In vivo animal experiments for RS2 are not extensively described in the available literature. As a research compound, its use in vivo would be determined by the specific research question being addressed. A typical protocol for studying a PDK1 inhibitor like RS2 would involve its administration to animal models of cancer or metabolic diseases. The compound would be formulated for injection, likely using a vehicle that includes DMSO, PEG, and saline. It could be administered via intraperitoneal (i.p.) or intravenous (i.v.) injection at a predetermined dose and schedule. Endpoints would include assessment of S6K1 phosphorylation, tumor growth, or metabolic parameters. However, specific protocols for RS2 are not detailed in the available literature.
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| ADME/Pharmacokinetics |
RS2 has a molecular weight of 380.89 g/mol and a molecular formula of C15H9ClN2O2S3. It has a logP of 5.2. The compound is supplied as a white to light yellow solid powder. It is soluble in DMSO at approximately 125 mg/mL (328.18 mM). For storage, it is recommended to keep the powder at -20°C for up to 3 years or at 4°C for up to 2 years. In solvent, it can be stored at -80°C for 6 months or at -20°C for 1 month. The compound is stable at ambient temperature for a few days during shipping. Detailed pharmacokinetic properties such as half-life, bioavailability, and tissue distribution have not been extensively characterized.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for RS2 is not provided in standard product descriptions. As a research compound, its toxicity profile has not been extensively characterized. RS2 is a substrate-selective inhibitor of PDK1, and its toxicity would be related to its effects on PDK1-mediated signaling pathways in normal tissues. As with all research chemicals, standard laboratory safety precautions should be followed when handling RS2. Its use is limited to research applications and it is not intended for human or veterinary use.
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| References | |
| Additional Infomation |
RS2 (PDK1-IN-RS2) is a research compound and is not approved for any clinical or therapeutic use. It is a small-molecule inhibitor of PDK1 that functions as a bioactive mimetic of the peptide docking motif (PIFtide). RS2 is a substrate-selective PDK1 inhibitor with a Kd of 9 µM. It suppresses the activation of downstream kinase S6K1 by PDK1 without affecting AKT activation. RS2 is a unique tool for dissecting PDK1 signaling pathways that rely on the PIF-pocket docking mechanism. A co-crystal structure of RS2 with PDK1 is available (PDB: 4RQV, 1.50 Å). RS2 is used to study PDK1 signaling and its role in cell growth, metabolism, and cancer. Its mechanism of action involves binding to the PIF-pocket of PDK1 and selectively inhibiting the activation of PIF-pocket-dependent substrates.
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| Molecular Formula |
C15H9CLN2O2S3
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| Molecular Weight |
380.892158269882
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| Exact Mass |
379.951
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| CAS # |
1643958-89-7
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| PubChem CID |
86290242
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| Appearance |
White to light yellow solid powder
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
541
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC2=C(C=1)SC(=N2)NS(C1=CC2C=CC=CC=2S1)(=O)=O
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| InChi Key |
MZAVPBQCWWIYEQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H9ClN2O2S3/c16-10-5-6-11-13(8-10)22-15(17-11)18-23(19,20)14-7-9-3-1-2-4-12(9)21-14/h1-8H,(H,17,18)
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| Chemical Name |
N-(6-chloro-1,3-benzothiazol-2-yl)-1-benzothiophene-2-sulfonamide
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| Synonyms |
RS2 R S 2 R-S-2
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~328.18 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6254 mL | 13.1271 mL | 26.2543 mL | |
| 5 mM | 0.5251 mL | 2.6254 mL | 5.2509 mL | |
| 10 mM | 0.2625 mL | 1.3127 mL | 2.6254 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05743790 | COMPLETED | Dietary Supplement: RS2-control-RS4 Dietary Supplement: RS4-control-RS2 |
Healthy Volunteers | Cornell University | 2019-09-26 | Not Applicable |
| NCT05528575 | COMPLETED | Dietary Supplement: Blueberry, cranberry, green tea extract, cocoa Dietary Supplement: GOS, Inulin, RS2 Dietary Supplement: prebiotics and polyphenols Dietary Supplement: Maltodextrin |
Gut Bacteria Stress, Psychological |
University of Reading | 2022-01-01 | Not Applicable |
| NCT00679848 | COMPLETED | Device: RS2 (RESTORe Suturing System) | Obesity | C. R. Bard | 2008-05 | Phase 1 |
| NCT05272046 | ACTIVE, NOT RECRUITING | Procedure: Per-oral Endoscopic Myotomy
Device: Speedboat (Bipolar electrocautery knife) |
Esophageal Motility Disorders | Baylor College of Medicine | 2022-02-22 | Not Applicable |
| NCT01229527 | COMPLETEDWITH RESULTS | Drug: Remifentanil Drug: Remifentanil Drug: Meperidine |
Colonoscopy | Ospedale San Raffaele | 2009-04 | Phase 4 |
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