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MDV3100 (Enzalutamide)Androgen receptor antagonist

MDV3100 (Enzalutamide)

Catalog No. A3003
Size Price Stock Qty
Evaluation Sample $28.00 In stock
5mg $90.00 In stock
10mg $160.00 In stock
25mg $280.00 In stock
50mg $480.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Product Citations

1. Bogner J, Zolghadr K, et al. "The fluorescent two-hybrid assay for live-cell profiling of androgen receptor modulators." J Steroid Biochem Mol Biol. 2016 May 9. PMID:27174722

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Chemical structure

MDV3100 (Enzalutamide)

Related Biological Data

MDV3100
KLK3 (top) and NKX3-1(bottom) expression which were the AR target genes in various resistant clones were analyzed by QPCR. All lines were pretreated with vehicle (?) or doxycycline (+) for 3 days before treatment with DMSO (left) or 10 μmol/L MDV3100 (right) for 24 hours in 10% FCS. TBP was used to normalize expression. Data represent mean ± SEM; n = 3. *, P < 0.05; **, P < 0.01 (Student t test). The F876L mutation is suf?cient to induce genetic and phenotypic resistance to MDV3100.

Review (Georgia Regents University)

MDV3100
Comparison of different anti-androgen/AR compounds on TGF-β1/Smad3/MMP9 signaling in PCa cells. CWR22Rv1 cells treated with 10 μM CASO, 10 μM MDV, 10 μM ASC, 5 μM CTS, or vehicle for 3 days were harvested. The expressions of TGF-β1, p-Smad3, Smad3, MMP9, and GAPDH were analyzed by Western blot analysis. All of the experiments have been repeated twice independently. *, p< 0.05; **, p < 0.01; ***, p < 0.001. Error bars, S.D. Casodex and MDV3100 enhanced TGF-beta, MMP9 expression in CWR22Rv1 cells. whereas ASC-J9 and CTS treatment did not.

Review (University of Glasgow )

MDV3100
Chronic exposure to ENZA resulted in autophagy. To mimic resistant to ENZA, C4-2B cells were subjected to 20 μM ENZA over a period of 3 months and selected for a sub-population of resistance cells (C4-2B+R). Upper panel showed acridine orange staining of autophagosome acidic vesicles as a marker for autophagy. Lower panel showed LC3-I/II protein expression in parental cells (control) and under chronic ENZA exposure-treated vehicle control, chloroquine (CQ) or CMI. β -Actin was used as the loading control.

Related Biological Data

MDV3100 (Enzalutamide)
F2H assay facilitates dose-response profiling of antiandrogens and DHT in endpoint assays and in live cells. (A) F2H analysis compares concentration-dependent effects of abiraterone, bicalutamide, enzalutamide, flutamide, and TOK-001 on the wt AR N/C interaction induction by 0.25 nM DHT. (B) Time-lapse images show induction of the interaction between the wt AR-LBD and AR-NTD in two living mammalian cells upon incubation with 0.25 nM DHT, followed by disruption of the interaction within 4 h after addition of 10 μM bicalutamide. (C) Dose-response F2H analysis demonstrates that theinhibitory effects of 10 μM bicalutamide, enzalutamide, flutamide, and TOK-001 depend on the DHT concentration. J Steroid Biochem Mol Biol. 2016 May 9.

Related Biological Data

MDV3100 (Enzalutamide)

Biological Activity

Description Enzalutamide (MDV3100) is an antagonist of androgen-receptor (AR) with IC50 of 36 nM.
Targets Androgen-receptor          
IC50 36 nM          

Protocol

Cell experiment:[1]

Cell lines

VCaP, LNCaP, 22RV1, DU145 and PC3 prostate cancer cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

10 μM,12h

Applications

Recruitment of AR to target loci was markedly attenuated by MDV3100 and less so by bicalutamide. Interestingly, JQ1 blocked AR recruitment almost as effectively as MDV3100. Limiting our evaluationto AR and BRD4 coincident peaks, we observed that DHT-mediated AR recruitment to these loci was inhibited by MDV3100 and to a lesser extent by JQ1. Corroborating the ChIP seq data, gene expression analysis in VCaP and LNCaP cells showed more efficient repression of DHT-induced AR-target genes by JQ1 than by MDV3100 or bicalutamide.

Animal experiment:[1]

Animal models

Four-week-old male SCIDC.B17 mice

Dosage form

10 mg/kg,oral gavage or intraperitonially,five days a week

Application

Treatment of VCaP tumour-bearing mice with JQ1 led to a significant reduction in tumour volume/weight, whereas MDV3100 had a less pronounced effect. Recently, several studies described the pro-metastatic effects of MDV3100 in pre-clinical models. To test whether MDV3100 treatment leads to spontaneous metastasis in our VCaP xenograft model, we isolated femur,  liver and spleen from MDV3100-treated mice and found evidence of metastases in femur and liver. By contrast, JQ1-treated mice showed no evidence of metastasis. Taken together, these pre-clinical studies suggest that the use of MDV3100 in clinically localized prostate cancer may potentiate the formation of micro-metastases, unlike BET inhibitors.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Phase III experiment [2]:

Target

Men with castration-resistant prostate cancer

Dosage form

160 mg per day (800 patients) or placebo (399 patients)

Application

The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001),  radiographic  progression-free  survival  (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group.

References:

1. Asangani IA, Dommeti VL, Wang X et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014 Jun 12;510(7504):278-82.

2. Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97.

MDV3100 (Enzalutamide) Dilution Calculator

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Chemical Properties

Cas No. 915087-33-1 SDF Download SDF
Synonyms Enzalutamide, MDV3100, MDV-3100, MDV 3100
Chemical Name 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-fluoro-N-methylbenzamide
Canonical SMILES CC1(C(=O)N(C(=S)N1C2=CC(=C(C=C2)C(=O)NC)F)C3=CC(=C(C=C3)C#N)C(F)(F)F)C
Formula C21H16F4N4O2S M.Wt 464.4
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Research Update

1. Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer. Ther Adv Urol. 2013 Aug;5(4):201-10. doi: 10.1177/1756287213490054.
Abstract
As an approved agent for the treatment of mCRPC, enzalutamide, an oral inhibitor of androgen receptor, does not require administration with steroids and was well tolerated in randomized phase III AFFIRM study.
2. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer. 2013 Dec;49(18):3821-30. doi: 10.1016/j.ejca.2013.09.026. Epub 2013 Oct 24.
Abstract
The cross-resistance between taxanes (docetaxel and cabazitaxel) and new hormonal agents (abiraterone and enzalutamide) and their effects on AR nuclear translocation have been investigated.
3. Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Prostate. 2013 Sep;73(12):1291-305. doi: 10.1002/pros.22674. Epub 2013 Jun 13.
Abstract
Enzlutamide is an inhibitor of AR signaling that inhibits multiple steps of AR signaling, blocks the growth of CRPC cells and increases survival in patients with metastatic CRPC.
4. Enzalutamide for the treatment of castration-resistant prostate cancer. Drugs Today (Barc). 2013 Jan;49(1):7-13. doi: 10.1358/dot.2013.49.1.1910724.
Abstract
In preclinical studies, enzalutamide blocks androgen signaling and the bind of AR to DNA leading to apoptosis and slowed tumor growth; while, in clinical trials, it exhibited significant antitumor activity with an optimal safety profile and significantly improved survival in metastatic CRPC male patients with prior chemotherapy.
5. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013 Jul;24(7):1802-7. doi: 10.1093/annonc/mdt138. Epub 2013 Apr 12.
Abstract
Although Abiraterone acetate and enzalutamide improve outcomes in metastatic mCRPC patients individually, optimal sequencing and occurrence of cross-resistance in combination therapy are unknown.

Background

MDV3100, known as Enzalutamide, is a second-generation androgen receptor (AR) signaling inhibitor. It has been demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. It is able to inhibit binding of androgens to the AR, AR nuclear translocation, and the association of the AR with DNA. The AR is a 919-amino acid member of the steroid receptor transcription factor superfamily with different domains including an N-terminal regulation domain, a central DNA binding domain, and a C-terminal domain, which includes the ligand-binding domain incorporated within its protein structure. MDV3100 was identified by the Sawyers/Jung laboratories by using the nonsteroidal agonist. Testing was showing that it induced apoptosis in VCaP cells, an AR gene amplified human prostate cancer line, while bicalutamide was ineffective.

Reference

Howard I. Scher, Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N. Sternberg, Kurt Miller, Ronald De Wit, Peter Mulders, Mohammad Hirmand, Bryan Selby, Johann Sebastian. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. Journal of Clinical Oncology. 2012; 30(5):

Manoj P. Menon, Celestia S. Higano. Enzalutamide, a Second Generation Androgen Receptor Antagonist: Development and Clinical Applications in Prostate Cancer. Current Oncology Reports. 2013; 15(2): 69 – 75.

Joelle El-Amm, Nihar Patel, Ashley Freeman, Jeanny B. Aragon-Ching. Metastatic Castration-Resistant Prostate Cancer: Critical Review of Enzalutamide. Clinical Medicine Insights: Oncology. 2013; 7: 235 – 245.