tcsc0334 Galeterone

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 K_d 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].