Galeterone

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Galeterone 是一种口服生物可利用的小分子雄激素受体调节剂和 CYP17 裂合酶抑制剂，具有潜在的抗雄激素活性。

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).

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%.

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).

TOK001 | NX 41765 | VN-1241 | Galeterone.

Others

Other Targets

Androgen Receptor| CYP17

Cancer

——

851983-85-2

388.55

C26H32N2O

>98% (HPLC)

DMSO : 18 mg/mL. 46.33 mM;

C[C@]12CC[C@@H](CC1=CC[C@@H]1[C@@H]2CC[C@]2([C@H]1CC=C2n1cnc2ccccc12)C)O

(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

(-20℃)

With Ice Pack

≥ 2 years