Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor

Citations Over TimeTop 10% of 2014 papers

Abstract

The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.

Related Papers

• → Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy(2014)192 cited
• → Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide(2016)55 cited
• → TAS 3681, an androgen receptor antagonist, prevents drug resistance driven by aberrant androgen receptor signaling in prostate cancer(2024)8 cited
• → 457 Preclinical pharmacology of AZD5312, a generation 2.5 antisense oligonucletotide targeting the androgen receptor with differentiated activity from enzalutamide(2014)4 cited
• → Supplementary Figure 2 from NF-κB2/p52 Induces Resistance to Enzalutamide in Prostate Cancer: Role of Androgen Receptor and Its Variants(2023)