title: Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain.
abstract: Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity. Inhibitors of AR AF-1 would potentially block most AR mechanisms of resistance including constitutively active AR splice variants that lack the ligand-binding domain. Here we provide evidence that sintokamide A (SINT1) binds AR AF-1 region to specifically inhibit transactivation of AR NTD. Consistent with SINT1 targeting AR AF-1, it attenuated transcriptional activities of both full-length AR and constitutively active AR splice variants, which correlated with inhibition of growth of enzalutamide-resistant prostate cancer cells expressing AR splice variants. In vivo, SINT1 caused regression of CRPC xenografts and reduced expression of prostate-specific antigen, a gene transcriptionally regulated by AR. Inhibition of AR activity by SINT1 was additive to EPI-002, a known AR AF-1 inhibitor that is in clinical trials (NCT02606123). This implies that SINT1 binds to a site on AF-1 that is unique from EPI. Consistent with this suggestion, these two compounds showed differences in blocking AR interaction with STAT3. This work provides evidence that the intrinsically disordered NTD of AR is druggable and that SINT1 analogs may provide a novel scaffold for drug development for the treatment of prostate cancer or other diseases of the AR axis.
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Carmen A
authors: CA
authors: Banuelos
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Iran
authors: I
authors: Tavakoli
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Amy H
authors: AH
authors: Tien
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Daniel P
authors: DP
authors: Caley
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Nasrin R
authors: NR
authors: Mawji
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada, Institute of Clinical Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors: Zhenzhen
authors: Z
authors: Li
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Jun
authors: J
authors: Wang
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Yu Chi
authors: YC
authors: Yang
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors: Yusuke
authors: Y
authors: Imamura
authors: Chemistry and Earth and Ocean Sciences, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada, and.
authors: Luping
authors: L
authors: Yan
authors: Urodynamic Center, First Affiliated Hospital of Zhengzhou, Zhengzhou University Hospital, Zhengzhou, Henan 450052, China.
authors: Jian Guo
authors: JG
authors: Wen
authors: Chemistry and Earth and Ocean Sciences, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada, and.
authors: Raymond J
authors: RJ
authors: Andersen
authors: From the Department of Genome Sciences Centre, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada, msadar@bcgsc.ca.
authors: Marianne D
authors: MD
authors: Sadar
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000072417:Protein Domains; D011760:Pyrrolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D059002:Androgen Receptor Antagonists; D009363:Neoplasm Proteins; D011760:Pyrrolidinones; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C556981:sintokamide A
keywords: androgen receptor; drug development; intrinsically disordered protein; prostate cancer; steroid hormone receptor; transcription factor