Discovery of novel antagonists targeting the DNA binding domain of
androgen receptor by integrated docking-based virtual screening and
bioassays
Abstract
Background and Purpose: Androgen receptor (AR), a ligand-activated
transcription factor, is a master regulator in the development and
progress of prostate cancer (PCa). A major challenge for the clinically
used AR antagonists is the rapid emergence of resistance induced by some
point mutations in the AR ligand binding domain (LBD), and therefore
discovery of novel anti-AR therapeutics that can combat mutation-induced
resistance is quite demanding. Therein, blocking the interaction between
AR and DNA represents an innovative strategy to overcome resistance of
traditional antagonists towards the AR LBD. Experimental Approach: In
this study, an integrated docking-based virtual screening (VS) strategy
based on the crystal structure of the DNA binding domain (DBD) of AR was
conducted to search for novel AR antagonists, and then a series of
bioassays including bio-layer interferometry (BLI) and RNA-seq were used
to evaluate the biological activities of these compounds. Key Results:
Among the tested compounds,
2-(2-butyl-1,3-dioxoisoindoline-5-carbox-amido)-4,5-dimeth-oxybenzoicacid
(Cpd39) was identified as a potential hit, which was competent to block
the binding of the AR DBD to androgen receptor response (ARE) and showed
decent potency against AR transcriptional activity. Furthermore, Cpd39
was capable of effectively inhibiting the proliferation of PCa cell
lines (i.e., LNCaP, PC3, DU145, and 22RV1) and reducing the expression
of not only the full-length AR but also the splice variant AR-V7.
Conclusion and Implications: The novel AR DBD-ARE blocker Cpd39 could
serve as a starting point for the development of new therapeutics for
castration-resistant PCa.