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

Rosati, Rayna; Polin, Lisa A.; 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 E.; Ratnam, Manohar

Abstract

Purpose: Testosterone suppression in prostate cancer (PC) is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for ARdependent growth in various hormone-dependent and castration resistant PC models. The amino terminal domain of AR docks at two sites on ELK1 to co-activate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of PC, 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 PC 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 6h and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-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.

Citation

Rosati, R., Polin, L. A., Ducker, C., Li, J., Bao, X., Selvakumar, D., Kim, S., Xhabija, B., Larsen, M., McFall, T., Huang, Y., Kidder, B. L., Fribley, A., Saxton, J., Kakuta, H., Shaw, P. E., & Ratnam, M. (2018). Strategy for tumor selective disruption of androgen receptor function in the spectrum of prostate cancer. Clinical Cancer Research, https://doi.org/10.1158/1078-0432.ccr-18-0982

• Journal Article Type: Article
• Acceptance Date: Aug 31, 2018
• Online Publication Date: Sep 5, 2018
• Publication Date: Sep 5, 2018
• Deposit Date: Sep 27, 2018
• Publicly Available Date: Sep 6, 2019
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1158/1078-0432.ccr-18-0982
• Keywords: Prostate cancer; Castration resistance; Androgen receptor; ELK1; Drug discovery
• Public URL: https://nottingham-repository.worktribe.com/output/1136607
• Publisher URL: http://clincancerres.aacrjournals.org/content/early/2018/09/05/1078-0432.CCR-18-0982
• Contract Date: Sep 27, 2018