Galeterone (TOK-001, VN/124-1) is a selective CYP17 inhibitor and androgen receptor (AR) antagonist with IC50 of 300 nM and 384 nM, respectively. Galeterone is effective at preventing binding of [3H]-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant AR (T877A) in LNCaP cells and the wild-type AR in PC-3AR cells. Galeterone potently inhibits the AR-mediated transcription in LNCaP cells transiently transfected with a probasin luciferase reporter construct AARZ-Luc in a concentration-dependent manner. Galeterone inhibits the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC50 of <10 μM. Galeterone is very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft. In the LAPC4 xenograft, Galeterone is a more potent agent in reducing tumor growth than other compounds (VN/85, VN/87, and VN108) and is more effective than castration and casodex. Treatment with Galeterone markedly reduces AR protein levels both in vivo and in vitro. Thus, Galeterone disrupts androgen receptor (AR) signaling via a novel triple mechanism of action (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). Galeterone also inhibits the growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Additionally, Galeterone in combination with thapsigargin exhibits synergistic effect in inhibiting PC-3 cell growth. Galeterone in combination with everolimus or gefitinib demonstrates superior synergy for growth inhibition against hormone-refractory prostate cancer cell line (high-passage LNCaP, HP-LNCaP) compared with bicalutamide. Dual inhibition of AR and mTOR with Galeterone and everolimus acts in concert to reduce tumor growth rates in the castration-resistant prostate cancer xenograft model. Galeterone is a superior inhibitor than abiraterone of R1881-induced transcriptional activity of both wild type and mutant AR.
| Molecular Weight | 388.55 |
| Formula | C26H32N2O |
| CAS Number | 851983-85-2 |
| Solubility (25°C) | DMSO 18 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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