TOK-001

CYP17 inhibitor and androgen receptor (AR) antagonist CAS# 851983-85-2

TOK-001

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Chemical structure

TOK-001

3D structure

Chemical Properties of TOK-001

Cas No. 851983-85-2 SDF Download SDF
PubChem ID 11188409 Appearance Powder
Formula C26H32N2O M.Wt 388.56
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 25 mg/mL (64.34 mM; Need ultrasonic)
Chemical Name (3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol
SMILES CC12CCC(CC1=CCC3C2CCC4(C3CC=C4N5C=NC6=CC=CC=C65)C)O
Standard InChIKey PAFKTGFSEFKSQG-PAASFTFBSA-N
Standard InChI InChI=1S/C26H32N2O/c1-25-13-11-18(29)15-17(25)7-8-19-20-9-10-24(26(20,2)14-12-21(19)25)28-16-27-22-5-3-4-6-23(22)28/h3-7,10,16,18-21,29H,8-9,11-15H2,1-2H3/t18-,19-,20-,21-,25-,26-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of TOK-001

DescriptionGaleterone(TOK-001) is a selective inhibitor of CYP17 and antagonist of androgen receptor (AR) with IC50 value of 300 nM and 384 nM, respectively
TargetsCYP17Androgen Receptor    
IC50300 nM384 nM    

TOK-001 Dilution Calculator

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Preparing Stock Solutions of TOK-001

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.5736 mL 12.868 mL 25.7361 mL 51.4721 mL 64.3401 mL
5 mM 0.5147 mL 2.5736 mL 5.1472 mL 10.2944 mL 12.868 mL
10 mM 0.2574 mL 1.2868 mL 2.5736 mL 5.1472 mL 6.434 mL
50 mM 0.0515 mL 0.2574 mL 0.5147 mL 1.0294 mL 1.2868 mL
100 mM 0.0257 mL 0.1287 mL 0.2574 mL 0.5147 mL 0.6434 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on TOK-001

TOK-001 (Galeterone) is a novel small molecule that selectively target CYP17 and androgen receptor for prostate cancer treatment [1].

CYP17 and androgen receptor (AR) are two preferred target during the treatment of prostate cancer: The former is the prime enzyme that responsible for the production of cancer-inducing androgens [1], whereas the latter acts as transcription factor that increases the expression of androgen-responsive genes [2].

Galeterone is a small molecular therapeutics that designed to treat prostate cancer in three distinctive pathways: competitively inhibit the enzyme function of CYP17. Decreasing androgen-responsive genes expression by binding to AR, and downregulates AR population [3]. Using 293T cells transfected with CYP17, galeterone inhibited the lyase function of CYP17 with an IC50 value of 47 nM after 18 hrs of incubation [3]. In prostate cancer cell line assay, galeterone inhibited the proliferation of LNCaP and LAPC-4 with IC50 value of 6 and 3 µM, respectively [3].

In mice xenograft model that inoculated with LAPC4 cell lines, a daily subcutaneous injection of galeterone (0.15 mmol/kg, twice per day) reduced both the average volume and weight of tumour less by more than 80% and 50%, respectively in comparison with control group [3]. Galeterone is currently underwent phase III clinical trails for castration-resistant prostate cancer.

References:
[1]. Devore N M, & Scott E E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature, 2012, 482: 116-119.
[2]. Mallik I, Davila M, Tapia T, et al. Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008,1783:1737-1744.
[3]. Bruno R D, Vasaitis T S, Gediya L. K, et al. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids, 2011,76: 1268-1279.

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References on TOK-001

Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer.[Pubmed:25591066]

J Med Chem. 2015 Mar 12;58(5):2077-87.

In our effort to discover potent and specific inhibitors of 17alpha-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes the biosynthesis of androgens from progestins, 3beta-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate which modulates multiple targets in the androgen receptor (AR) signaling pathway. This drug annotation summarizes the mechanisms of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for galeterone, which has successfully completed phase II clinical development in men with castration resistant (advanced) prostate cancer (CRPC). Phase III clinical studies in CRPC patients are scheduled to begin in early 2015.

Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.[Pubmed:22266943]

Nature. 2012 Jan 22;482(7383):116-9.

Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans. As prostate cancer cells proliferate in response to androgen steroids, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer, or TOK-001, an inhibitor that is currently undergoing clinical trials. Both of these inhibitors bind the haem iron, forming a 60 degrees angle above the haem plane and packing against the central I helix with the 3beta-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme's dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.

Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model.[Pubmed:21729712]

Steroids. 2011 Nov;76(12):1268-79.

In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3xi-fluoro-) and 9 (3beta-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was approximately 2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.

Comparisons of Prostate Cancer Inhibitors Abiraterone and TOK-001 Binding with CYP17A1 through Molecular Dynamics.[Pubmed:26682016]

Comput Struct Biotechnol J. 2015 Nov 4;13:520-7.

Cytochrome P450 17A1 (CYP17A1) is associated in the steroid hormone biosynthesis in human. As cell proliferation of prostate cancer in response to androgen steroid, an inhibition of CYP17A1 becomes an alternative approach to inhibit biosynthesis of androgen and support treatment of prostate cancer. However, biology-driven inhibitor development of prostate cancer is poorly elucidated. The aims of this study are to address structural differences at atomic-level between CYP17A1 and inhibitors i.e., abiraterone and TOK-001, and further investigate the effect of point mutation of CYP17A1 on the active site stability and the local interactions that are hydrophobic interaction and hydrogen bonding throughout molecular dynamics (MD) simulation. After performing multiple comparisons among four different complexes across CYP17A1 and inhibitors, interestingly TOK-001 oriented toward the active pocket and formed larger volume with I-helix of CYP17A1 than abiraterone, whereas abiraterone showed tighter binding and more active site stability. Considering on the effect of hydrophobic interaction and hydrogen bonding between abiraterone and CYP17A1, the key residues of Phe114, Ile371, Val482, and Asn202 were identified. This contributes into tight binding interactions; however abiraterone is effectively weakened along with the global conformation mobility increased in A105L mutation. Surprisingly, overall conformation of the CYP17A1 remained stable when bound to TOK-001. This basic knowledge can guide future experiments on design of efficient inhibitors for CYP17A1, which provides theoretical basis of androgen-dependent disease therapy.

Description

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

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