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

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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Troglitazone	Approved Investigational Withdrawn	AR	367	downregulated	troglitazone results in decreased expression of AR mRNA	Xq12
Troglitazone	Approved Investigational Withdrawn	CIDEC	63924	upregulated	troglitazone results in increased expression of CIDEC mRNA	3p25.3
Troglitazone	Approved Investigational Withdrawn	KLK3	354	downregulated	troglitazone results in decreased expression of KLK3 mRNA	19q13.33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