Faculty Collaboration Database

Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer. Clin Cancer Res 2018 Dec 15;24(24):6509-6522

Date

09/07/2018

Pubmed ID

30185422

Pubmed Central ID

PMC6295231

DOI

10.1158/1078-0432.CCR-18-0982

Scopus ID

2-s2.0-85058440559 (requires institutional sign-in at Scopus site)   14 Citations

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 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.

Author List

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

Author

Thomas Mcfall PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Androgen Receptor Antagonists
Animals
Antineoplastic Agents, Hormonal
Cell Line, Tumor
Disease Models, Animal
Drug Discovery
Drug Screening Assays, Antitumor
Gene Expression Profiling
High-Throughput Screening Assays
Humans
Male
Mice
Promoter Regions, Genetic
Prostatic Neoplasms
Protein Binding
Receptors, Androgen
Structure-Activity Relationship
Xenograft Model Antitumor Assays
ets-Domain Protein Elk-1