1. Metabolic Enzyme/Protease
  2. Cytochrome P450

TOK-001 (Synonyms: VN/124-1; Galeterone; VN 124)

Cat. No.: HY-70006 Purity: 99.14%
Handling Instructions

TOK-001 is a multifunctional antiandrogen and CYP17 inhibitor (IC50=47 nM) in castration resistant prostate cancer (CRPC).

For research use only. We do not sell to patients.

TOK-001 Chemical Structure

TOK-001 Chemical Structure

CAS No. : 851983-85-2

Size Price Stock Quantity
Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO USD 66 In-stock
Stock in the United States
Estimated Time of Arrival: December 31
5 mg USD 60 In-stock
Stock in the United States
Estimated Time of Arrival: December 31
10 mg USD 90 In-stock
Stock in Sweden
Estimated Time of Arrival: December 31
50 mg USD 270 In-stock
Stock in Sweden
Estimated Time of Arrival: December 31
100 mg USD 450 In-stock
Stock in the United States
Estimated Time of Arrival: December 31
200 mg USD 650 In-stock
Stock in the United States
Estimated Time of Arrival: December 31
500 mg USD 1150 In-stock
Stock in the United States
Estimated Time of Arrival: December 31
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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

TOK-001 is a multifunctional antiandrogen and CYP17 inhibitor (IC50=47 nM) in castration resistant prostate cancer (CRPC).

IC50 & Target

IC50: 47 nM (CYP17)[1]

In Vitro

TOK-001 affords strong CYP17 lyase inhibition, with IC50 of 47 nM[1]. TOK-001 is both a CYP17A1 inhibitor and androgen receptor antagonist and the similarity of these binding modes is likely the reason for this dual mechanism of action.This CYP17A1 binds abiraterone and TOK-001 with absorbance decreases at 402 nm and increases at 424 nm, consistent with nitrogen binding to the heme iron (type II interaction) with Kd of <100 nM[2]. When LNCaP cells are cultured in medium supplemented with charcoal-stripped serum (CSS, T<1 nM) followed by treatment with increasing concentrations of TOK-001, the steady-state levels of AR protein are markedly decreased (up to 84%, 15 μM TOK-001). In LAPC-4 cells, abiraterone alcohol reduced AR expression to a greater extent than TOK-001 at concentrations greater than or equal to 1 μM. When LNCaP cells are treated with 20 μM TOK-001 for 24 h, AR mRNA levels are reduced by 38%[3].

In Vivo

Mice inoculated with LAPC-4 tumors are treated subcutaneously with 0.15 mmol/kg of TOK-001 twice daily. Mice treated with TOK-001 have smaller average tumor volume on day 31 when compared to control (p= 0.0001). TOK-001 treatment also significantly reduces the growth rate of tumor growth compared to control (p<0.0001). Upon excision, final tumor weights are also significantly reduced in animals treated with TOK-001 compared to animals treated with control, and castration (p<0.05)[1].

Clinical Trial
References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 2.5737 mL 12.8684 mL 25.7367 mL
5 mM 0.5147 mL 2.5737 mL 5.1473 mL
10 mM 0.2574 mL 1.2868 mL 2.5737 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[2]

Progesterone 17α-hydroxylation is evaluated using a modified HPLC method with UV-detection. CYP17A1 (50 pmol) and rat NADPH-cytochrome P450 reductase 1:4 are mixed, incubated on ice (20 minutes), and added to buffer (50 mM Tris, pH 7.4 and 5 mM MgCl2) containing progesterone (0-50 μM) to a total volume of 500 μL. Phosphatidylcholine (25 μg) is included for side-by-side kinetic comparisons with the full-length enzyme. For IC50 determinations, inhibitors concentrations are 0-1500 nM for abiraterone and 0-3000 nM for TOK-001 (Shanghai Haoyuan Chemexpress Co., Shanghai, China). After warming (37°C, 3 minutes), reactions are initiated by NADPH addition (20 μL 25 mM), incubated for 10 minutes (37°C), and quenched with 20% trichloroacetic acid (300 μL) and placed on ice. The 17α-hydroxyprogesterone metabolite is identified by UV detection at 248 nm following HPLC separation and coeluted with authentic standards. The HPLC mobile phase is 40% acetonitrile, 60% water with 1% acetic acid and run at 1 mL/min (Phenomenex, Luna 5 μ, C18, 50×4.6 mm)[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[3]

TOK-001 is dissolved with DMSO and diluted with appropriate media[3].

LNCaP cells are seeded in 24-well plates at 70% confluence a day before transfections. Cells then are transfected with plasmid DNA (0.5 μg/well) carrying pIR-AR 5′UTR-Luc (5′UTR; test) or pIRES-Luc (IRES, control) for 6 h in serum-free and antibiotic-free conditions. Transcription of both luciferase reporter genes is under the control of the CMV promoter. Lipofectamine 2000 reagent is used in all transfections according to the manufacturer's instructions. Cells are then treated with doses of TOK-001 (0, 10, and 20 μM) in 5% FBS/T-Medium. Luciferase reporter gene activities are measured using Luciferase Assay System from Promega at 36 h post treatment using a BMG Labtech microplate reader. Relative luciferase units are normalized to total protein and then normalized to vector control (pIR-AR 5′UTR-Luc) and the result is presented as luciferase activity. For cell proliferation studies, LNCaP cells in 96-well plate are seeded 24 h prior to drug treatment and then treated with control (mock), TOK-001 (10 μM), or abiraterone alcohol (10 μM) in 5% FBS/T-medium for 72 h. Cell proliferation is determined using MTS[3]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

TOK-001 is dissolved in DMSO and then diluted with saline or PBS[1].

Mice[1]
Mice inoculated with LAPC-4 tumors are treated subcutaneously with 0.15 mmol/kg of TOK-001 twice daily. Mice treated with TOK-001 have smaller average tumor volume on day 31 when compared to control (p=0.0001). TOK-001 treatment also significantly reduced the growth rate of tumor growth compared to control (p<0.0001). Upon excision, final tumor weights are also significantly reduced in animals treated with TOK-001 compared to animals treated with control, and castration (p<0.05). MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

388.55

Formula

C₂₆H₃₂N₂O

CAS No.

851983-85-2

SMILES

C[[email protected]@]12C(N3C=NC4=CC=CC=C34)=CC[[email protected]]1([[email protected]@]5(CC=C6[[email protected]@](C)([[email protected]]5(CC2)[H])CC[[email protected]@H](C6)O)[H])[H]

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: 18 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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Product Name:
TOK-001
Cat. No.:
HY-70006
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