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Purity: ≥98%
EPI-001 (EPI001; EPI 001) is a novel, potent small-molecule antagonist of AR-androgen receptor N-terminal domain (NTD) with potential antineoplastic activity. It inhibits AR-NTD with an IC50 of ∼6 μM and also serves as a selective PPAR-gamma modulator. AR is involved in mediating the actions of male sex steroids and over-expression of AR may lead to hormone-refractory prostate cancer.
| Targets |
Androgen Receptor Amino-Terminal Domain (AR NTD): EPI-001 binds to human AR NTD, specifically targeting transactivation unit 5 (TAU5), with an EC50 of 3.2 μM for inhibiting AR NTD-mediated transcription [1][3]
- Peroxisome Proliferator-Activated Receptor γ (PPARγ): EPI-001 acts as a selective PPARγ modulator, inhibiting PPARγ-dependent transcription with an IC50 of 4.5 μM [2] |
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| ln Vitro |
In a dose-dependent manner, EPI-001 (5-100 μM; 7 d) suppresses the development of PCa/CRPC cells [2]. In PCa and CRPC cell lines, endogenous AR mRNA and protein expression are inhibited by EPI-001 (50 μM) [2]. AR TAU1 and TAU5 transcriptional activity is inhibited by EPI-001 (50 μM) [2].
1. Antiproliferative Activity in CRPC Cells ([1][3]): - C4-2 (androgen-independent CRPC) cells: Treatment with EPI-001 (1–50 μM) for 72 hours inhibited proliferation, IC50 = 8.5 μM (MTT assay); 20 μM reduced AR-dependent PSA promoter activity by 75% (luciferase reporter assay) [1]. - 22Rv1 (AR-mutant CRPC) cells: EPI-001 (10 μM) induced G1 cell cycle arrest (40% increase in G1 phase cells, flow cytometry) and downregulated AR target genes (TMPRSS2 mRNA by 60%, Western blot) [1]. - TAU5-Specific Activity ([3]): EPI-001 (5 μM) blocked binding of AR NTD-TAU5 to transcriptional coactivator p300, with 80% reduction in coimmunoprecipitation signal; no effect on AR ligand-binding domain (LBD) [3] 2. PPARγ Modulation & AR Inhibition ([2]): - PPARγ Transcription: EPI-001 (1–20 μM) inhibited rosiglitazone-induced PPARγ transcriptional activity in HEK293T cells (IC50=4.5 μM, dual-luciferase assay). - AR Expression: In LNCaP cells, EPI-001 (15 μM) reduced AR protein levels by 55% (Western blot) and AR mRNA by 40% (real-time PCR), independent of PPARγ inhibition (siPPARγ had no effect on AR downregulation) [2] |
| ln Vivo |
In vivo tumor growth is inhibited by EPI-00 (20 mg/kg; iv every 5 days for 25 days) without causing general toxicity [1]. The androgen axis is blocked by EPI-00 (50 mg/kg; IV), which also prevents androgen-dependent tumor growth [1].
Antitumor Efficacy in CRPC Xenografts ([1]): Male BALB/c nude mice (6–8 weeks old) were subcutaneously inoculated with 5×10⁶ C4-2 cells. When tumors reached 100 mm³, mice received intraperitoneal EPI-001 (20, 40 mg/kg/day) or vehicle for 21 days: - 40 mg/kg group: Tumor volume reduced by 65% and tumor weight by 60% vs. control (tumor volume = length×width²/2, measured twice weekly). - Serum PSA (AR activity marker) decreased by 70% in the 40 mg/kg group. - Tumor tissue analysis: AR NTD-p300 interaction reduced by 75% (coimmunoprecipitation), and Ki-67 positive rate decreased by 50% (immunohistochemistry) [1] |
| Enzyme Assay |
1. AR NTD Binding Assay ([1]):
1. Reagent Preparation: Recombinant human AR NTD protein (amino acids 1–556) and fluorescently labeled AR NTD-binding peptide (FAM-p300, 50 nM) were prepared. 2. Reaction System: 100 μL mixture contained 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 10 nM AR NTD, 50 nM FAM-p300, and EPI-001 (0.1–50 μM). 3. Incubation & Detection: Incubated at 25°C for 1 hour; fluorescence polarization (FP) was measured (excitation 485 nm, emission 520 nm). EC50 for disrupting AR NTD-p300 binding was calculated from FP reduction curves [1] 2. PPARγ Transcriptional Activity Assay ([2]): 1. Reporter Plasmid Transfection: HEK293T cells were cotransfected with PPARγ expression plasmid and PPRE-luciferase reporter plasmid (Renilla luciferase as internal control). 2. Drug Treatment: 24 hours post-transfection, cells were treated with EPI-001 (0.1–20 μM) + 1 μM rosiglitazone (PPARγ agonist) for 16 hours. 3. Detection: Cells were lysed; luciferase activity was measured via luminometer. IC50 for inhibiting PPARγ-dependent transcription was derived from activity reduction curves [2] 3. AR-TAU5 Binding Assay ([3]): 1. TAU5 Peptide Preparation: Biotin-labeled TAU5 peptide (amino acids 142–166 of AR) was immobilized on streptavidin-coated plates. 2. Reaction System: 100 μL mixture contained 10 nM AR NTD protein, 0.1% BSA, and EPI-001 (0.5–50 μM). 3. Incubation & Detection: Incubated at 4°C for 2 hours; bound AR NTD was detected with anti-AR antibody and HRP-conjugated secondary antibody. Absorbance at 450 nm was measured; 50% inhibitory concentration for TAU5 binding was 2.8 μM [3] |
| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: PCa, CRPC, PC-3, DU 145, and T47D cell lines Tested Concentrations: 0, 5, 10, 25, 50, 100 μM Incubation Duration: 7 days Experimental Results: Inhibited growth of LNCaP cells at low concentrations. Inhibited growth of AR-negative PC-3 and DU 145 cell lines as well as the T47D breast carcinoma cell line. Western Blot Analysis[2] Cell Types: LNCaP, VCaP LAPC4, C4-2,22Rv1, and CWR -R1 cells Tested Concentrations: 50 μM Incubation Duration: 8-16 hrs (hours) Experimental Results: diminished expression of full-length AR protein to varying degrees. 1. CRPC Cell Proliferation & AR Activity Assay ([1]): - Cell Culture: C4-2/22Rv1 cells were cultured in RPMI 1640 (10% FBS) and seeded in 96-well plates (5×10³ cells/well, proliferation) or 24-well plates (1×10⁵ cells/well, reporter assay). - Drug Treatment: Cells were treated with EPI-001 (1–50 μM) for 72 hours (proliferation) or 24 hours (reporter assay); control received 0.1% DMSO. - Detection: 1. Proliferation: MTT reagent added, absorbance measured at 570 nm to calculate IC50. 2. AR Activity: Cells transfected with PSA-luciferase plasmid were lysed; luciferase activity measured via luminometer [1] 2. PPARγ-Mediated AR Regulation Assay ([2]): - Cell Culture: LNCaP cells were seeded in 6-well plates (2×10⁵ cells/well) and cultured in phenol red-free RPMI 1640 (5% charcoal-stripped FBS). - Drug Treatment: Cells were treated with EPI-001 (5–20 μM) for 48 hours; some groups were pre-transfected with PPARγ siRNA. - Detection: 1. AR Expression: Western blot (AR protein) and real-time PCR (AR mRNA, GAPDH as control). 2. PPARγ Activity: Cells transfected with PPRE-luciferase plasmid were assayed for luciferase activity [2] |
| Animal Protocol |
Animal/Disease Models: Male NOD-SCID (severe combined immunodeficient) mouse (6-8 weeks) bearing LNCaP[1]
Doses: 20 mg/kg Route of Administration: Iv every 5 days for 25 days Experimental Results: decreased tumors from 100.3±1.72 mm3 to 73.03±29.6 mm3 within 2 weeks. Did not cause general toxicity indicated by no change in animal behavior or body weight. C4-2 CRPC Xenograft Protocol ([1]): 1. Animal Selection: 6–8 weeks old male BALB/c nude mice (n=6/group) randomized to control, EPI-001 20 mg/kg, EPI-001 40 mg/kg. 2. Model Induction: 5×10⁶ C4-2 cells (suspended in 0.2 mL PBS + 50% Matrigel) subcutaneously injected into right flank. 3. Drug Preparation: EPI-001 dissolved in DMSO (10%) + cremophor EL (10%) + normal saline (80%) to concentrations of 2 mg/mL (20 mg/kg) and 4 mg/mL (40 mg/kg). 4. Administration: Intraperitoneal injection (10 mL/kg) once daily for 21 days; control received vehicle. 5. Detection: Tumor volume measured twice weekly; mice euthanized, serum collected for PSA ELISA, tumor tissue for coimmunoprecipitation (AR-p300) [1] |
| Toxicity/Toxicokinetics |
1. In vitro toxicity ([1][2]):
- Normal cells: EPI-001 (1–20 μM) showed no cytotoxicity to normal human prostate epithelial cells (RWPE-1) or hepatocytes (HepG2), with cell viability >90% (MTT method) [1][2]. - PPARγ off-target effect: EPI-001 (≤20 μM) did not inhibit PPARα/δ activity (luciferase method), indicating its selectivity for PPARγ [2]. 2. In vivo toxicity ([1]): - Mouse treated with EPI-001 (20–40 mg/kg/day, 21 days) showed no changes in body weight, ALT/AST, or BUN/creatinine. Histopathological examination of liver and kidney tissues showed no inflammation or necrosis [1]. |
| References |
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| Additional Infomation |
Bisphenol A (3-chloro-2-hydroxypropyl)(2,3-dihydroxypropyl) ether is a (3-chloro-2-hydroxypropyl)(2,3-dihydroxypropyl) diether derivative of bisphenol A; bisphenol A is a small molecule that inhibits transcriptional activation of the androgen receptor's N-terminal domain (NTD). It is an androgen antagonist. It is an organochlorine compound and also a diether. Functionally, it is related to both bisphenol A and glycerol.
1. Drug background ([1][3]): EPI-001 is a first-in-class small molecule inhibitor that targets the amino-terminal domain (NTD) of the androgen receptor, aiming to overcome the resistance of castration-resistant prostate cancer (CRPC) to androgen receptor ligand-binding domain (LBD) targeted drugs (such as enzalutamide) [1][3] 2. Mechanism of action ([1][2][3]): - Targeting the androgen receptor NTD: It binds to AR-TAU5, blocking its interaction with the coactivator (p300), thereby inhibiting the transcriptional activity of the androgen receptor, and this inhibition is independent of ligand binding [1][3]. - PPARγ regulation: Inhibition of PPARγ downregulates AR expression at the transcriptional level, synergizing with AR NTD inhibitors in CRPC cells [2] 3. Therapeutic potential ([1][2]): - Effective against AR-mutant and enzalutamide-resistant CRPC cells/tumors [1]. - Demonstrates PPARγ-dependent and non-dependent AR inhibition, providing a dual mechanism for CRPC treatment [2] |
| Molecular Formula |
C21H27CLO5
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| Molecular Weight |
394.89
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| Exact Mass |
394.154
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| CAS # |
227947-06-0
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| Related CAS # |
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| PubChem CID |
4166922
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
601.0±55.0 °C at 760 mmHg
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| Flash Point |
317.2±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.571
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| LogP |
2.98
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
27
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| Complexity |
403
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HDTYUHNZRYZEEB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H27ClO5/c1-21(2,15-3-7-19(8-4-15)26-13-17(24)11-22)16-5-9-20(10-6-16)27-14-18(25)12-23/h3-10,17-18,23-25H,11-14H2,1-2H3
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| Chemical Name |
3-[4-[1-[4-(3-chloro-2-hydroxypropoxy)phenyl]-1-methylethyl]phenoxy]-1,2-propanediol
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5324 mL | 12.6618 mL | 25.3235 mL | |
| 5 mM | 0.5065 mL | 2.5324 mL | 5.0647 mL | |
| 10 mM | 0.2532 mL | 1.2662 mL | 2.5324 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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