Modulation of nuclear receptor function: Targeting the protein-DNA interface. (15th March 2019)

• Record Type: Journal Article
• Authors: Veras Ribeiro Filho, Helder; Tambones, Izabella Luisa; Mariano Gonçalves Dias, Marieli; Bernardi Videira, Natalia; Bruder, Marjorie; Amorim Amato, Angélica; Migliorini Figueira, Ana Carolina
• Is Part Of: Molecular and cellular endocrinology. Volume 484(2019)
• Page Start: 1
• Page End: 14
• Publication Date: 2019-03-15
• Subjects: Nuclear receptors modulation -- DNA binding domain -- DNA response elements -- NRs alternative binding sites -- Polyamides; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2019.01.023
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that modulate several biological processes. Traditionally, modulation of NRs has been focused on the development of ligands that recognize and bind to the ligand binding domain (LBD), resulting in activation or repression of transcription through the recruitment of coregulators. However, for more severe diseases, such as breast and prostate cancer, the conventional treatment addressing LBD modulation is not always successful, due to tumor resistance. To overcome these challenges and aiming to modulate NR activity by inhibiting the NR-DNA interaction, new studies focus on the development of molecules targeting alternative sites and domains on NRs. Here, we discuss two different approaches for this alternative NR modulation: one targeting the NR DNA binding domain (DBD); and the other targeting the DNA sites recognized by NRs. Our aim is to present the challenges and perspectives for developing specific inhibitors for each purpose, alongside with already reported examples. Highlights: The DNA-binding domain and DNA are targets to inhibit the Nuclear Receptor-DNA interaction. DNA-interface and dimerization inhibitors can impair the Nuclear Receptor-DNA interaction. Polyamides are a tool to inhibit the Nuclear Receptor-DNA interaction. Selectivity for the DNA-binding domain or DNA is a challenge in rational drug design.