EPI-001

EPI-001 is a small-molecule inhibitor of androgen receptor N-terminal domain. EPI-001 could target the amino terminal domain of the AR and inhibit the protein-protein interactions which are necessary for AR transcriptional activity. The androgen receptor (AR) is involved in mediating the actions of male sex steroids. Amplification and over-expression of androgen receptor gene may result in hormone-refractory prostate cancer [1].

In vitro: EPI-001 inhibited the ligand-dependent ARGal4 transcriptional activity in LNCaP cells and the ligand-independent ARGal4 transcriptional activity in the CRPC C4-2 cell line. In a panel of cell lines, EPI-001 treatment decreased the mRNA expression level of AR protein after 8 and 16 h treatment, such as androgen sensitive PCa, CRPC, LNCap, C4-2, and LAPC4 cell line. EPI-001 dose-dependently inhibited the PCa/CRPC cell growth [2].

In vivo: Intravenous injection of EPI-001 significantly reduced the weight of benign prostates and blocked the growth of prostate cancer xenograft from noncastrated mature mice. EPI-001 caused tumor regression of CRPC. In male mice bearing LNCaP xenografts, after treated with EPI- 001 by i.v. injection for 2 weeks, the tumor size was less than half of the control group [3].

References:
Andersen R J, Mawji N R, Wang J, et al.  Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor[J]. Cancer cell, 2010, 17(6): 535-546.
Brand L J, Olson M E, Ravindranathan P, et al.  EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer[J]. Oncotarget, 2015, 6(6): 3811.
Sadar M D.  Small molecule inhibitors targeting the “achilles' heel” of androgen receptor activity[J]. Cancer research, 2011, 71(4): 1208-1213.

EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.[Pubmed:25669987]

Oncotarget. 2015 Feb 28;6(6):3811-24.

The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARgamma). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR NTD, and reduced AR expression. EPI-001 inhibited growth of AR-positive and AR-negative PCa cell lines, with the highest sensitivity observed in LNCaP cells. Overall, this study provides new mechanistic insights to the chemical biology of EPI-001, and raises key issues regarding the use of covalent inhibitors of the intrinsically unstructured AR NTD.

Matrix-assisted laser desorption mass spectrometry imaging for the examination of imipramine absorption by Straticell-RHE-EPI/001 an artificial model of the human epidermis.[Pubmed:21480772]

Xenobiotica. 2011 Aug;41(8):735-42.

In order to assess the potential of matrix-assisted laser desorption mass spectrometry imaging for the examination of artificial skin models, the absorption of the tricyclic antidepressant imipramine into Straticell-RHE-EPI/001 an artificial model of the human epidermis has been studied. The presence of imipramine could be clearly discerned in treated samples by imaging the distribution of the protonated molecule at m/z 281.18 in samples taken 2 and 8 h after treatment. No clear evidence of biotransformation of imipramine in the artificial epidermal model was detected, although some signals that could potentially be assigned to the desmethyl metabolite were detected. Further work is required in order to investigate the reasons for the apparent low levels of metabolites detected.

Successful micronucleus testing with the EPI/001 3D reconstructed epidermis model: preliminary findings.[Pubmed:22266475]

Mutat Res. 2012 Mar 18;743(1-2):36-41.

Currently, the cosmetics industry relies on the results of in vitro genotoxicity tests to assess the safety of chemicals. Although the cytokinesis-block micronucleus (CBMN) test for the detection of cells that have divided once is routinely used and currently accepted by regulatory agencies, it has some limitations. Reconstituted human epidermis (RHE) is widely used in safety assessments because its physiological properties resemble those of the skin, and because it allows testing of substances such as hydrophobic compounds. Thus, the micronucleus test is being adapted for application in RHE-reconstructed tissues. Here we investigated whether two different reconstructed epidermis models (EPI/001 from Straticell, and RHE/S/17 from Skinethic) are suitable for application of the micronucleus test. We found that acetone does not modify micronucleus frequency, cell viability, and model structure, compared with non-treated RHE. Treatment of the EPI/001 model with mitomycin C and vinblastine resulted in a dose-dependent increase of micronucleus frequency as well as a decrease of tissue viability and of binucleated cell rate, while no changes of the epidermal structure were observed. The number of binucleated cells obtained with the RHE/S/17 model was too small to permit micronucleus testing. These results indicate that the proliferative rate of the tissue used is a critical parameter in performing the micronucleus test on a 3D model.

EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.[Pubmed:27356095]

ACS Chem Biol. 2016 Sep 16;11(9):2499-505.

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.