| Size | Price | Stock | Qty |
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| 1mg |
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| 100mg | |||
| Other Sizes |
| Targets |
PAC targets estrogen receptor-alpha (ERalpha) when conjugated to an antibody that targets ERalpha-expressing cells. The compound combines the targeting capability of an antibody with the protein degradation activity of a PROTAC. The PROTAC component recruits an E3 ubiquitin ligase to induce ubiquitination and subsequent proteasomal degradation of ERalpha. By conjugating the PROTAC to an antibody, PAC achieves targeted delivery to ERalpha-expressing cells, enhancing degradation efficacy and reducing off-target effects.
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| ln Vitro |
HER2 antibodies including PAC Anti-HER2 (Endox-XIAP) significantly reduced the levels of estrogen receptor alpha (ERα) in HER2-expressing cells, with an IC50 of 132 ng/mL. PROTAC-antibody conjugate (PAC) molecules are made up of an antibody attached to a PROTAC through a linker (L1); the PROTAC is made up of a protein binding group, a linker ("L2"), and a ubiquitin E3 ligase binding group ("E3LB"). group ("PB"). The elements that comprise the PAC are explained in the sections that follow. These components are offered in order to create a PAC with optimal therapeutic index and effective efficacy. 1. Antibodies (Ab): While PACs containing antibodies against non-antigens reside on the cell surface, the antibody portion of PAC can target cells expressing the antigen, thereby delivering antigen-specific PACs to target cells intracellularly, usually by endocytosis. Pinocytosis of the PAC may still occur, but the identification of the PROTAC moiety may lead to less targeted intracellular transport of the PROTAC moiety. 2. Linker (L1): To create a PAC, one or more PROTAC moieties (D) can be linked to an antibody (Ab) by a "linker" (L1), which is a bifunctional or multifunctional moiety. L1 with reactive functional groups for covalent attachment to PROTAC and antibodies can be used in some embodiments to prepare PAC. 3. PROTAC(D) [1].
In vitro, PAC conjugated to an antibody is a more marked ERalpha degrader compared to PROTAC alone. The antibody conjugation enhances the delivery of the PROTAC to ERalpha-expressing cells, resulting in more efficient degradation of the target protein. The compound's activity is typically assessed in cell-based assays measuring ERalpha protein levels by Western blotting or immunofluorescence. Its targeted degradation mechanism makes it a valuable tool for studying ERalpha biology and developing targeted cancer therapies. |
| ln Vivo |
In vivo studies of PAC are focused on evaluating its efficacy in animal models of ERalpha-positive cancers. As an antibody-conjugated PROTAC, it is designed to achieve targeted degradation of ERalpha in tumor tissues while minimizing systemic effects. The antibody conjugation enhances tumor targeting and retention. Further in vivo studies are needed to fully characterize its pharmacokinetic properties, bioavailability, and efficacy in various cancer models. The compound represents a novel approach to targeted protein degradation.
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| Enzyme Assay |
For in vitro binding and degradation assays, PAC can be evaluated using binding studies to confirm its interaction with ERalpha and the E3 ubiquitin ligase. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used to measure binding affinities. The compound's ability to induce ERalpha ubiquitination and degradation is assessed in cell-based assays. ERalpha protein levels are measured by Western blotting. The enhanced degradation efficacy of antibody-conjugated PAC compared to unconjugated PROTAC is quantified.
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| Cell Assay |
For in vitro cellular experiments, PAC is tested in ERalpha-positive cell lines to evaluate its degradation efficacy and effects on cell viability. Cells are cultured in appropriate media and treated with various concentrations of the antibody-conjugated PAC or unconjugated PROTAC. ERalpha protein levels are assessed by Western blotting or immunofluorescence. Cell viability and proliferation are evaluated using standard assays. The compound's effects on ERalpha-dependent gene expression are analyzed by qPCR. The enhanced degradation efficacy of antibody-conjugated PAC is compared to PROTAC alone.
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| Animal Protocol |
For in vivo animal experiments, PAC can be administered to tumor-bearing mice via intravenous injection as an antibody-conjugated construct. Xenograft models using ERalpha-positive human cancer cell lines are commonly used to evaluate antitumor efficacy. Typical dosing regimens may range from 1 to 50 mg/kg. Tumor volume is measured regularly, and tumor growth inhibition is calculated. ERalpha protein levels in tumors are assessed by immunohistochemistry or Western blotting. Pharmacodynamic markers and gene expression changes are measured.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of PAC are influenced by its antibody conjugation. As a large molecule with a molecular weight of 1674.93 for the small molecule component plus the antibody, it would have a long half-life in circulation typical of antibody-based therapeutics. The antibody conjugation provides targeted delivery and prolonged exposure. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies of the antibody-conjugated construct.
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| Toxicity/Toxicokinetics |
Toxicological data for PAC are limited, as it is a research tool for targeted protein degradation. As an antibody-conjugated PROTAC targeting ERalpha, its toxicity would depend on the expression of ERalpha in normal tissues and the specificity of the antibody. Comprehensive toxicology studies including acute and repeated-dose toxicity, immunogenicity, and off-target degradation assessments would be needed for further development. Appropriate safety precautions should be taken when handling this compound.
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| References | |
| Additional Infomation |
PAC is a research compound used for targeted protein degradation studies. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound consists of an ADC linker and a PROTAC designed for antibody conjugation. PAC conjugated to an antibody is a more marked ERalpha degrader compared to PROTAC alone.
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| Molecular Formula |
C94H107N13O16
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|---|---|
| Molecular Weight |
1674.93290352821
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| Exact Mass |
1674.799
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| CAS # |
2158322-33-7
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| Related CAS # |
PROTAC ERα Degrader-1;2417369-94-7
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| PubChem CID |
132144829
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| Appearance |
White to off-white solid powder
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| LogP |
10.2
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
18
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| Rotatable Bond Count |
43
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| Heavy Atom Count |
123
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| Complexity |
3550
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| Defined Atom Stereocenter Count |
5
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| SMILES |
C(C1C=CC(C(=O)NCCOCCOCC(=O)N(C)CCOC2C=CC(C(C3C=CC(OCC4C=CC(NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)CCCCCN5C(C=CC5=O)=O)=CC=4)=CC=3)=C(C3C=CC=CC=3)CC)=CC=2)=CC=1)(N1[C@H]([C@@H](C(=O)N(CC2=C(C=CC3C=CC=CC2=3)OC)C2=CC=C(C#N)C=C12)NC(=O)[C@H](C)NC)C)=O
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| InChi Key |
AAGUYPGVVXJDLD-GGHCKNFKSA-N
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| InChi Code |
InChI=1S/C94H107N13O16/c1-9-74(65-19-12-10-13-20-65)85(68-34-41-73(42-35-68)123-58-63-25-37-71(38-26-63)100-90(114)77(23-18-47-99-94(96)118)101-91(115)86(60(2)3)102-81(108)24-14-11-17-49-105-82(109)45-46-83(105)110)67-32-39-72(40-33-67)122-52-50-104(7)84(111)59-121-54-53-120-51-48-98-89(113)69-28-30-70(31-29-69)92(116)107-62(5)87(103-88(112)61(4)97-6)93(117)106(78-43-27-64(56-95)55-79(78)107)57-76-75-22-16-15-21-66(75)36-44-80(76)119-8/h10,12-13,15-16,19-22,25-46,55,60-62,77,86-87,97H,9,11,14,17-18,23-24,47-54,57-59H2,1-8H3,(H,98,113)(H,100,114)(H,101,115)(H,102,108)(H,103,112)(H3,96,99,118)/b85-74+/t61-,62-,77-,86-,87-/m0/s1
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| Chemical Name |
N-[2-[2-[2-[2-[4-[(Z)-1-[4-[[4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methoxy]phenyl]-2-phenylbut-1-enyl]phenoxy]ethyl-methylamino]-2-oxoethoxy]ethoxy]ethyl]-4-[(3S,4S)-7-cyano-1-[(2-methoxynaphthalen-1-yl)methyl]-4-methyl-3-[[(2S)-2-(methylamino)propanoyl]amino]-2-oxo-3,4-dihydro-1,5-benzodiazepine-5-carbonyl]benzamide
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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 Note: 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)
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| Solubility (In Vitro) |
DMSO : ~70 mg/mL (~41.79 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (1.49 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 1.75 mg/mL (1.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 17.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.5970 mL | 2.9852 mL | 5.9704 mL | |
| 5 mM | 0.1194 mL | 0.5970 mL | 1.1941 mL | |
| 10 mM | 0.0597 mL | 0.2985 mL | 0.5970 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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