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| Targets |
ERRα VHL
PROTAC ERRα Degrader-3 targets estrogen-related receptor alpha (ERRα), a nuclear receptor involved in energy metabolism, mitochondrial biogenesis, and cellular homeostasis. The compound functions as a PROTAC, recruiting the von Hippel-Lindau (VHL) E3 ubiquitin ligase to ERRα, leading to ubiquitination and subsequent proteasomal degradation of the target protein. It shows high selectivity for ERRα and is inactive against the closely related ERRβ and ERRγ proteins. This selective degradation enables precise modulation of ERRα activity without affecting other ERR family members. |
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| ln Vitro |
PROTAC ERRα Degrader-3 (Compound 6c; 0.3 nM-10 μM; 4 hours) stimulates ERRα degradation in a dose-dependent manner, with effective levels as low as 3.0 nM at 4.0 hours. PROTAC ERRα Degrader-3 efficiently lowered the protein levels of ERRα downstream target genes, such as ATP5B, medium-chain acyl-CoA dehydrogenase (MCAD), and pyruvate dehydrogenase kinase 4, in MDA-MB-231 cells after 24 hours of treatment. (PDK4)[1]. PROTAC ERRα Degrader-3 has an IC50 value of 12.67 nM and disrupts the protein-protein interaction of ERRα with PGC-1α peptide, generating approximately 96% protein degradation after 4.0 hours of treatment at 100 nM (D100 nM) [1].
In vitro, PROTAC ERRα Degrader-3 demonstrates potent and selective degradation of ERRα protein. At a concentration of 30 nM, the compound specifically degrades ERRα protein by >80%. The compound shows no activity against ERRβ and ERRγ proteins, demonstrating excellent selectivity. This selective degradation makes it a valuable tool for studying ERRα-specific functions and validating ERRα as a therapeutic target. The compound's activity is typically assessed in cell-based assays measuring ERRα protein levels by Western blot or immunofluorescence following treatment with varying concentrations. |
| ln Vivo |
Specific in vivo activity data for PROTAC ERRα Degrader-3 are not extensively documented in the publicly available literature. As a PROTAC molecule with a molecular weight of 956.99 g/mol, its in vivo efficacy would depend on factors such as oral bioavailability, tissue distribution, and target engagement. The compound's potent in vitro degradation activity suggests potential for in vivo applications in ERRα-driven disease models. Further studies are needed to characterize its in vivo pharmacokinetic and pharmacodynamic properties. The compound is intended for research use only.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for PROTAC ERRα Degrader-3 typically involve assessing the compound's ability to induce degradation of ERRα protein in cell-based systems rather than direct enzyme binding. The compound's activity is evaluated by measuring ERRα protein levels using Western blot or immunofluorescence after treatment with varying concentrations. Degradation efficacy is expressed as percentage of protein remaining or DC₅₀ values. The compound's selectivity is assessed by measuring protein levels of ERRβ and ERRγ to confirm inactivity against these targets. Assays are conducted under standard cell culture conditions with appropriate controls.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: MDA-MB-231 cells Tested Concentrations: 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM Incubation Duration: 4 hrs (hours) Experimental Results: Dose-dependently induced ERRα degradation. In vitro cell-based assays for PROTAC ERRα Degrader-3 utilize cell lines expressing endogenous ERRα or transfected with ERRα expression constructs. Cells are treated with varying concentrations of the compound for 6-24 hours. ERRα protein levels are measured by Western blot or high-content imaging to determine degradation efficacy. Selectivity is assessed by measuring ERRβ and ERRγ protein levels. Cell viability and proliferation can be evaluated using MTT or CCK-8 assays. Standard cell culture conditions (37°C, 5% CO₂) with appropriate media are employed. Dose-response curves are generated to determine DC₅₀ values. |
| Animal Protocol |
In vivo animal studies with PROTAC ERRα Degrader-3 would typically involve administration of the compound to rodent models to evaluate its efficacy in ERRα-driven disease models. Potential study designs include xenograft models using ERRα-dependent cancer cell lines, or metabolic disease models where ERRα plays a role. Typical endpoints would include tumor growth measurements, assessment of ERRα protein levels in target tissues, evaluation of downstream gene expression, and pharmacokinetic profiling. All procedures must comply with institutional animal care and use guidelines. Detailed published in vivo protocols are not currently available.
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| ADME/Pharmacokinetics |
Specific pharmacokinetic data for PROTAC ERRα Degrader-3 are not extensively documented in the publicly available literature. The compound has a molecular weight of 956.99 g/mol, which is relatively high for oral bioavailability. As a PROTAC molecule, its pharmacokinetic properties may be influenced by its bifunctional nature, which includes both a target-binding moiety and an E3 ligase-recruiting moiety. The compound is typically stored as a powder at -20°C. Information concerning product stability, particularly in solution, has rarely been reported. Further studies are needed to characterize its pharmacokinetic profile.
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| Toxicity/Toxicokinetics |
PROTAC ERRα Degrader-3 is intended for research use only and is not approved for human therapeutic applications. As a research chemical, comprehensive toxicological data are not available in the publicly accessible literature. Standard safety precautions should be observed when handling this compound, including the use of appropriate personal protective equipment. As with all research chemicals, comprehensive toxicological profiling would be required before any consideration for clinical development. The compound should be handled in well-ventilated areas with proper waste disposal procedures.
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| References | |
| Additional Infomation |
PROTAC ERRα Degrader-3 (CAS#: 2306388-65-6) has a molecular formula of C₄₇H₅₀F₆N₆O₇S and a molecular weight of 956.99 g/mol. Its IUPAC name is (2S,4R)-1-((S)-2-(5-((E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-cyanoacrylamido)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. It is a potent and selective ERRα degrader based on von Hippel-Lindau ligand, capable of degrading ERRα protein by >80% at 30 nM. It is inactive against ERRβ and ERRγ. This compound is not a drug and has not undergone clinical trials.
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| Molecular Formula |
C47H50F6N6O7S
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| Molecular Weight |
956.991331577301
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| Exact Mass |
956.336
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| CAS # |
2306388-65-6
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| PubChem CID |
155561684
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
7.5
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
18
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| Heavy Atom Count |
67
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| Complexity |
1760
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| Defined Atom Stereocenter Count |
3
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| SMILES |
S1C=NC(C)=C1C1C=CC(=CC=1)CNC([C@@H]1C[C@H](CN1C([C@H](C(C)(C)C)NC(CCCCNC(/C(/C#N)=C/C1C=CC(=C(C=1)OC)OCC1C=CC(C(F)(F)F)=CC=1C(F)(F)F)=O)=O)=O)O)=O
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| InChi Key |
POTUUCUOBIVSIX-BDUCEWPUSA-N
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| InChi Code |
InChI=1S/C47H50F6N6O7S/c1-27-40(67-26-57-27)30-12-9-28(10-13-30)23-56-43(63)36-21-34(60)24-59(36)44(64)41(45(2,3)4)58-39(61)8-6-7-17-55-42(62)32(22-54)18-29-11-16-37(38(19-29)65-5)66-25-31-14-15-33(46(48,49)50)20-35(31)47(51,52)53/h9-16,18-20,26,34,36,41,60H,6-8,17,21,23-25H2,1-5H3,(H,55,62)(H,56,63)(H,58,61)/b32-18+/t34-,36+,41-/m1/s1
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| Chemical Name |
(2S,4R)-1-[(2S)-2-[5-[[(E)-3-[4-[[2,4-bis(trifluoromethyl)phenyl]methoxy]-3-methoxyphenyl]-2-cyanoprop-2-enoyl]amino]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide
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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: 80 mg/mL (83.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (2.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0449 mL | 5.2247 mL | 10.4494 mL | |
| 5 mM | 0.2090 mL | 1.0449 mL | 2.0899 mL | |
| 10 mM | 0.1045 mL | 0.5225 mL | 1.0449 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.
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