Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer

Abstract

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. Small-molecule drug discovery and extensive biological characterization of a lead compound. 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 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. 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.

De-ubiquitination of ELK-1 by USP17 potentiates mitogenic gene expression and cell proliferation

“…Nonetheless, our findings uncover an important functional relationship between USP17 and ELK-1 in its conserved role as ERK responder and activator of mitogenic gene expression (Figure 7F). Indeed, the impact of USP17 on ELK-1 function may extend beyond its relationship with ERK, given the recent discovery of a physical and functional cooperation between ELK-1 and androgen receptor in advanced prostate cancer (69,70). A next priority will be to identify the ubiquitin E3 ligase(s) specifically responsible for mono-ubiquitination of ELK-1.…”

Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development

“…Moreover, expression of a hypo-ubiquitinated ELK-1 mutant, but not wild-type ELK-1, partially rescued the proliferation defect caused by USP17 depletion in HEK293T cells, illustrating the contribution of this mechanism towards mitogen signalling [ 86 ]. The established role for ELK-1 as an AR tethering element suggests that further studies are warranted to decipher whether USP17 acts on ELK-1 to promote tumorigenesis in PCa [ 91 , 92 , 93 ].…”

The Potential of Cammelia sinensis (Tea Leaves) Active Compound as Alternative Therapy on castrate-resistant prostate cancer (CRPC) with Androgen Receptor Inhibition: In Silico Study

“…15 Research by Siddiqui et al showed that the green tea compound epigallocatechin-3-gallate could inhibit AR in silico and inhibit cell lines from prostate cancer. 16,17 In this study, only one extracted compound from green tea was tested and it did not use ADT control for comparison with AR.…”