Galeterone

Galeterone 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. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17, 20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. (In Vitro) :Galeterone (TOK-001) affords strong CYP17 lyase inhibition, with IC50 of 47 nM. 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) .