Modulation of nuclear receptor function: Targeting the protein-DNA interface

Author(s)

Ribeiro Filho, Helder Veras ^{[1, 2]} ; Tambones, Izabella Luisa ^{[1, 2]} ; Goncalves Dias, Marieli Mariano ^{[1, 3]} ; Videira, Natalia Bernardi ^[1] ; Bruder, Marjorie ^[1] ; Amato, Angelica Amorim ^[4] ; Migliorini Figueira, Ana Carolina ^[1]

Affiliation

^[1] CNPEM, Brazilian Ctr Res Energy & Mat, LNBio, Brazilian Biosci Natl Lab, BR-13083970 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Inst Biol, Grad Program Biosci & Technol Bioact Prod, BR-13083970 Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Inst Biol, Grad Program Mol & Funct Biol, BR-13083970 Campinas, SP - Brazil

^[4] Univ Brasilia, UnB, Dept Pharmaceut Sci, Lab Mol Pharmacol, BR-70910900 Brasilia, DF - Brazil

• Document type: Review article
• Source: Molecular and Cellular Endocrinology; v. 484, p. 1-14, MAR 15 2019.
• Web of Science Citations: 3

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. (AU)

• FAPESP's process: 16/22246-0 - PPAR gamma repression mechanism as a target to combat diabetes and obesity
• Grantee: Ana Carolina Migliorini Figueira
• Support type: Regular Research Grants
• FAPESP's process: 18/02481-0 - Regulation of the SMyHC iii promoter by the nuclear receptors AR, GR and Coup-TFII: a solo or joint work?
• Grantee: Izabella Luisa Tambones
• Support type: Scholarships in Brazil - Master