Abstract
Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40–50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
Highlights
Nuclear receptors (NRs) are a pharmacologically relevant superfamily of transcription factors implicated in numerous human conditions [1]
Our results indicate that Atro-box binding site represents a promising target to regulate TLX
The cell lines were maintained in the following culture media: DU145: Dulbecco’s Modified Eagles Medium (DMEM) (Hyclone, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% Fetal Bovine Serum (FBS); LNCaP, PC3, BPH1,C42, and PC3M: RPMI
Summary
Nuclear receptors (NRs) are a pharmacologically relevant superfamily of transcription factors implicated in numerous human conditions [1]. TLX could induce resistance to androgen-deprivation through molecule inhibitors of TLX could potentially have high therapeutic value in the number of human direct suppression of AR gene transcription and signaling in PCa cells [23]. We were the first to perform virtual screening of small molecules by docking of Zinc database [35] into the Atro-box binding pocket of human TLX. Following in vitro characterization characterization of the top-ranked hits allowed us to identify three chemicals capable to inhibit TLX transcriptional activity in the μmolar range in three a dose-dependent manner. Of the top-ranked hits allowed us to identify chemicals capable to inhibit TLX transcriptional activity in the μmolar range in a dose-dependent manner
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