Galeterone

Galeterone, also known as TOK-001 and NX41765; is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling.

Product information

CAS Number: 851983-85-2

Molecular Weight: 388.55

Formula: C26H32N2O

Synonym:

TOK-001

NX-41765

VN-1241

Chemical Name: (3S,8R,9S,10R,13S,14S)-17-(1H-benzo[d]imidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol

Smiles: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC=C2N1C=NC2=CC=CC=C12

InChiKey: PAFKTGFSEFKSQG-PAASFTFBSA-N

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

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

Galeterone (TOK-001) affords strong CYP17 lyase inhibition, with IC50 of 47 nM[1]. Galeterone (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 Galeterone (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. When LNCaP cells are cultured in medium supplemented with charcoal-stripped serum (CSS, T<1 nM) followed by treatment with increasing concentrations of Galeterone (TOK-001), the steady-state levels of AR protein are markedly decreased (up to 84%, 15 μM Galeterone (TOK-001)). In LAPC-4 cells, abiraterone alcohol reduced AR expression to a greater extent than Galeterone (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%.

In Vivo:

Mice inoculated with LAPC-4 tumors are treated subcutaneously with 0.15 mmol/kg of Galeterone (TOK-001) twice daily. Mice treated with TOK-001 have smaller average tumor volume on day 31 when compared to control (p= 0.0001). Galeterone (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 Galeterone (TOK-001) compared to animals treated with control, and castration (p<0.05).

References:

1. Gomez L, Kovac JR, Lamb DJ. CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids. 2015 Jan 3. pii: S0039-128X(14)00314-6. doi: 10.1016/j.steroids.2014.12.021. [Epub ahead of print] PubMed PMID: 25560485.
2. Gupta E, Guthrie T, Tan W. Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC). BMC Urol. 2014 Jul 25;14:55. doi: 10.1186/1471-2490-14-55. PubMed PMID: 25062956; PubMed Central PMCID: PMC4167156.
3. Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J. New agents for prostate cancer. Ann Oncol. 2014 Sep;25(9):1700-9. doi: 10.1093/annonc/mdu038. Epub 2014 Mar 20. PubMed PMID: 24658665.

Products are for research use only. Not for human use.