EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.
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Brand LJ, Olson ME, Ravindranathan P, Guo H, Kempema AM, Andrews TE, Chen X, Raj GV, Harki DA, Dehm SM
EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer.
Oncotarget. 2015 Feb 28;6(6):3811-24.
- PubMed ID
- 25669987 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Troglitazone Approved Investigational Withdrawn AR 367 downregulated troglitazone results in decreased expression of AR mRNA Xq12 Troglitazone Approved Investigational Withdrawn CIDEC 63924 upregulated troglitazone results in increased expression of CIDEC mRNA 3p25.3 Troglitazone Approved Investigational Withdrawn KLK3 354 downregulated troglitazone results in decreased expression of KLK3 mRNA 19q13.33 Troglitazone Approved Investigational Withdrawn PDK4 5166 upregulated troglitazone results in increased expression of PDK4 mRNA 7q21.3 Troglitazone Approved Investigational Withdrawn TXNIP 10628 upregulated troglitazone results in increased expression of TXNIP mRNA 1q21.1