Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer

Rayna Rosati, Lisa Polin, Charles Ducker, Jing Li, Xun Bao, Dakshnamurthy Selvakumar, Seongho Kim, Besa Xhabija, Martha Larsen, Thomas McFall, Yanfang Huang, Benjamin L. Kidder, Andrew Fribley, Janice Saxton, Hiroki Kakuta, Peter Shaw, Manohar Ratnam

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1–AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental Design: Small-molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line–derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 30-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

Original languageEnglish
Pages (from-to)6509-6522
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
Publication statusPublished - Dec 15 2018

Fingerprint

Androgen Receptors
Prostatic Neoplasms
Neoplasms
Growth
flavone
Castration
Hydroxyl Radical
Testosterone
Essential Genes
Drug Discovery
Heterografts
Chromatin
Half-Life
Prostate
Rodentia
Research Design
Maintenance
Hormones
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer. / Rosati, Rayna; Polin, Lisa; Ducker, Charles; Li, Jing; Bao, Xun; Selvakumar, Dakshnamurthy; Kim, Seongho; Xhabija, Besa; Larsen, Martha; McFall, Thomas; Huang, Yanfang; Kidder, Benjamin L.; Fribley, Andrew; Saxton, Janice; Kakuta, Hiroki; Shaw, Peter; Ratnam, Manohar.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6509-6522.

Research output: Contribution to journalArticle

Rosati, R, Polin, L, Ducker, C, Li, J, Bao, X, Selvakumar, D, Kim, S, Xhabija, B, Larsen, M, McFall, T, Huang, Y, Kidder, BL, Fribley, A, Saxton, J, Kakuta, H, Shaw, P & Ratnam, M 2018, 'Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer', Clinical Cancer Research, vol. 24, no. 24, pp. 6509-6522. https://doi.org/10.1158/1078-0432.CCR-18-0982
Rosati, Rayna ; Polin, Lisa ; Ducker, Charles ; Li, Jing ; Bao, Xun ; Selvakumar, Dakshnamurthy ; Kim, Seongho ; Xhabija, Besa ; Larsen, Martha ; McFall, Thomas ; Huang, Yanfang ; Kidder, Benjamin L. ; Fribley, Andrew ; Saxton, Janice ; Kakuta, Hiroki ; Shaw, Peter ; Ratnam, Manohar. / Strategy for tumor-selective disruption of androgen receptor function in the spectrum of prostate cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6509-6522.
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AU - Rosati, Rayna

AU - Polin, Lisa

AU - Ducker, Charles

AU - Li, Jing

AU - Bao, Xun

AU - Selvakumar, Dakshnamurthy

AU - Kim, Seongho

AU - Xhabija, Besa

AU - Larsen, Martha

AU - McFall, Thomas

AU - Huang, Yanfang

AU - Kidder, Benjamin L.

AU - Fribley, Andrew

AU - Saxton, Janice

AU - Kakuta, Hiroki

AU - Shaw, Peter

AU - Ratnam, Manohar

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N2 - Purpose: Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1–AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental Design: Small-molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line–derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 30-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

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