title: Characterization of niphatenones that inhibit androgen receptor N-terminal domain.
abstract: Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD). Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD). Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S)-niphatenone had significantly better activity against the AR NTD compared to (R)-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR) activity and covalently bound to GR activation function-1 (AF-1) region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Banuelos
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Lal
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tien
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Neel
authors.initials: N
authors.lastname: Shah
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Yu Chi
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.affiliation: Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Labros G
authors.initials: LG
authors.lastname: Meimetis
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Park
authors.affiliation: Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Kunzhong
authors.affiliation: Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005995:Glyceryl Ethers / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000502:physiology; D013237:Stereoisomerism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D059002:Androgen Receptor Antagonists; D018931:Antineoplastic Agents, Hormonal; D005995:Glyceryl Ethers; D011944:Receptors, Androgen; C570921:niphatenone B; D015741:Metribolone