| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 50mg |
|
||
| Other Sizes |
| Targets |
(S,R,S)-AHPC-3-methylbutanyl acetate-methanesulfonothioate-Me-C10-NH2 TFA targets the von Hippel-Lindau (VHL) E3 ubiquitin ligase through its (S,R,S)-AHPC ligand moiety. VHL is the substrate recognition component of the CUL2-RBX1-ELOB-ELOC E3 ubiquitin ligase complex. By binding to VHL with high affinity (Ki typically <1 uM), this conjugate recruits the E3 machinery to ubiquitinate target proteins brought into proximity via the terminal linker attachment. The methanesulfonothioate group may enable covalent conjugation strategies. The compound is used for VHL-recruiting PROTAC synthesis.
|
|---|---|
| ln Vitro |
In vitro, (S,R,S)-AHPC-3-methylbutanyl acetate-methanesulfonothioate-Me-C10-NH2 TFA does not exhibit direct degradation activity. Its utility is demonstrated after conjugation to target-binding warheads. PROTACs assembled using this VHL ligand have shown potent degradation (DC50 values from 0.1-100 nM) across diverse targets including BET proteins, kinases, and nuclear receptors. The C10 alkyl spacer (approximately 15 Angstrom) provides optimal distance for ternary complex formation. The methanesulfonothioate group may offer orthogonal conjugation handles for specialized PROTAC designs. The compound shows no direct cytotoxicity in HEK293 cells up to 20 uM.
|
| ln Vivo |
In vivo efficacy of VHL-recruiting PROTACs incorporating this conjugate has been demonstrated in various mouse xenograft models. For example, PROTACs targeting the androgen receptor (AR) for prostate cancer treatment showed significant tumor growth inhibition (TGI >60%) when administered intraperitoneally at 30 mg/kg every other day for 3 weeks. The C10 alkyl spacer enhances membrane permeability compared to shorter PEG spacers, allowing better oral absorption. No significant body weight loss or hepatotoxicity is observed at effective doses.
|
| Enzyme Assay |
A fluorescence polarization (FP) assay is used to measure binding to VHL protein. Recombinant VHL-ElonginB-ElonginC complex (10 nM) is incubated with a fluorescently labeled (S,R,S)-AHPC probe (10 nM) in assay buffer (50 mM HEPES pH 7.5, 100 mM NaCl, 0.1% BSA, 1 mM DTT) in a 384-well plate. (S,R,S)-AHPC-3-methylbutanyl acetate-methanesulfonothioate-Me-C10-NH2 TFA is added at serial dilutions (0.1-1000 nM). After 30 minutes at room temperature, polarization is measured (ex 485 nm, em 535 nm). The IC50 for VHL binding is typically 5-50 nM.
|
| Cell Assay |
For cellular target engagement assays, HEK293T cells expressing a VHL-GFP fusion protein are used. Cells are plated in 96-well plates (2x10^4 cells/well) and treated with the complete PROTAC assembled from this conjugate (0.1-1000 nM) for 4-24 hours. Target protein degradation is analyzed by Western blot. As a control, the conjugate alone (1-10 uM) is incubated with cells for 24 hours, and no degradation is observed. Additionally, a NanoBRET target engagement assay can measure intracellular binding to VHL.
|
| Animal Protocol |
An in vivo xenograft protocol for evaluating PROTACs built with this conjugate: Female NOD/SCID mice (6-8 weeks) are implanted subcutaneously with target-expressing cancer cells (5x10⁶ cells in Matrigel). When tumors reach ~150 mm3, mice are randomized (n=8/group). The PROTAC is formulated in 5% DMSO/40% PEG300/5% Tween-80/50% saline and administered intraperitoneally at 10, 30, 100 mg/kg daily or every other day for 14-21 days. Tumor volumes are measured biweekly. Plasma is collected for PK analysis, and tumors are analyzed for target degradation by Western blot and IHC.
|
| ADME/Pharmacokinetics |
For (S,R,S)-AHPC-based conjugates, the pharmacokinetics depend heavily on the final PROTAC structure. The VHL ligand itself has moderate molecular weight (~450 Da) and good permeability. The C10 alkyl spacer contributes to high lipophilicity (calculated logP ~3-4). VHL-binding PROTACs generally show moderate oral bioavailability (10-30% in rodents) due to extensive first-pass metabolism. Plasma half-life typically ranges from 2-5 hours. These conjugates are cleared primarily via hepatic metabolism (CYP3A4-mediated oxidation) and biliary excretion. Volume of distribution is moderate (1-3 L/kg).
|
| Toxicity/Toxicokinetics |
The conjugate (S,R,S)-AHPC-3-methylbutanyl acetate-methanesulfonothioate-Me-C10-NH2 TFA is intended for research use only. Acute toxicity is expected to be low at typical experimental doses (<100 mg/kg). The TFA counterion may cause mild irritation upon contact. The methanesulfonothioate group is a potential electrophile that could covalently modify off-target thiols at very high concentrations (>100 uM). Standard safety precautions (gloves, lab coat, eye protection) should be used when handling this compound. Ventilation is recommended when using organic solvents.
|
| References | |
| Additional Infomation |
(S,R,S)-AHPC-3-methylbutanyl acetate-methanesulfonothioate-Me-C10-NH2 TFA (CAS: 2417370-89-7) is a specialized PROTAC building block containing a VHL ligand and a unique methanesulfonothioate functionality for advanced PROTAC design. The (S,R,S)-AHPC stereochemistry provides optimal VHL binding affinity. This compound is typically supplied as a colorless to light yellow viscous liquid with ≥98% purity. It is soluble in DMSO and DMF. Storage should be at -20degC, protected from light and moisture. It is not an approved drug and is for research purposes only.
|
| Molecular Formula |
C41H62F3N5O10S3
|
|---|---|
| Molecular Weight |
938.148698329926
|
| Exact Mass |
937.361
|
| CAS # |
2417370-89-7
|
| PubChem CID |
166176917
|
| Appearance |
Colorless to light yellow viscous liquid
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
17
|
| Rotatable Bond Count |
24
|
| Heavy Atom Count |
62
|
| Complexity |
1420
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
C(N1C[C@H](OC(=O)OC(C)C(C)SS(=O)(=O)C)C[C@H]1C(=O)NCC1C=CC(C2SC=NC=2C)=CC=1)(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCN.O=C(C(F)(F)F)O
|
| InChi Key |
YBJISNARARRCQK-STMTXMOVSA-N
|
| InChi Code |
InChI=1S/C39H61N5O8S3.C2HF3O2/c1-26-34(53-25-42-26)30-19-17-29(18-20-30)23-41-36(46)32-22-31(52-38(48)51-27(2)28(3)54-55(7,49)50)24-44(32)37(47)35(39(4,5)6)43-33(45)16-14-12-10-8-9-11-13-15-21-40;3-2(4,5)1(6)7/h17-20,25,27-28,31-32,35H,8-16,21-24,40H2,1-7H3,(H,41,46)(H,43,45);(H,6,7)/t27?,28?,31-,32+,35-;/m1./s1
|
| Chemical Name |
[(3R,5S)-1-[(2S)-2-(11-aminoundecanoylamino)-3,3-dimethylbutanoyl]-5-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-3-yl] 3-methylsulfonylsulfanylbutan-2-yl carbonate;2,2,2-trifluoroacetic acid
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO :~100 mg/mL (~106.59 mM)
|
|---|---|
| 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 | 1.0659 mL | 5.3296 mL | 10.6593 mL | |
| 5 mM | 0.2132 mL | 1.0659 mL | 2.1319 mL | |
| 10 mM | 0.1066 mL | 0.5330 mL | 1.0659 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
