MDV3100 is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. MDV3100 (Enzalutamide) blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Early preclinical studies also suggest that MDV3100 inhibits breast cancer cell growth.
|Cell lines||VCaP cell line|
|Preparation method||Proliferation assays Trypsinized VCaP cells were adjusted to a concentration of 100,000 cells per mL in phenol-red-free RPMI 1640 (with 5% CSS), and dispensed in 16 µL aliquots into CellBIND 384 well plates (Corning, Lowell, MA). Cells were incubated for 48 hours, after which ligand was added in a 16 µL volume to the RPMI culture medium. For the antagonist mode assay, the ligands were diluted in culture medium also containing 30 pM R1881 (final [R1881] = 15 pM). After 7 days’ incubation, 16 µL of CellTiter-Glo Luminescent Cell Viability Assay (Promega, Madison, WI) was added and Relative Luminescence Units (RLUs) measured. In the agonist mode assay, percent viability of the samples was calculated as: % viability=[RLU sample-RLU medium without cells]/[RLU DMSO treated cells-RLU medium without cells]. In the antagonist mode assay, the percent viability of the samples was calculated as: % viability=[RLU sample-RLU VCaP without R1881]/[RLU R1881-treated cells - RLU VCaP without R1881].|
|Animal models||LNCaP/AR(cs) xenograft model in mice|
|Formulation||prepared in 18% PEG-400, 1% Tween-80 and 1% povidone, and were formulated for dosing in 15% Vitamin E-TPGS and 65% of a 0.5% w/v CMC solution in 20 mM citrate buffer (pH 4.0).|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥91 mg/mL|
|Source||Mol Cancer Ther (2013). Figure 2. MDV3100|
|Cell Lines||LNCaP cells|
|Concentrations||0.01, 0.1, 1, 10, 100, 1000 μmol/L|
|Incubation Time||72 h|
|Results||We further investigated the effects on cell-cycle progression by analyzing the expression of cyclin D protein, which is known as aG1 phase cyclin that regulates the entry of cells intoG1, in Compound 30- and MDV3100-treated tumors|
|Source||Mol Cancer Ther (2013). Figure 1. MDV3100|
|Cell Lines||LNCaP cells|
|Incubation Time||24 h|
|Results||We found that Compound 30 decreased AR transcriptional activity, measured by probasin luciferase activity (Fig. 1B, top left), in a dose-dependent manner and with greater potency compared with MDV3100 [probasin 50% effective concentration (EC50): 12.5 and 20 mmol/L, respectively.|
Biomarker-based targeting of the androgen-androgen receptor axis in advanced prostate cancer.
Kohli et al. Adv Urol. 2012. PMID: 22956944.
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy.
Scher et al. N Engl J Med. 2012 Aug 15. PMID: 22894553.
Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born.
Schweizer et al. Ther Adv Urol. 2012 Aug;4(4):167-78. PMID: 22852027.
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