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Review
. 2019 Aug 1:493:110471.
doi: 10.1016/j.mce.2019.110471. Epub 2019 Jun 1.

Steroid receptor/coactivator binding inhibitors: An update

Kornelia J Skowron  1 , Kenneth Booker  1 , Changfeng Cheng  1 , Simone Creed  1 , Brian P David  1 , Phillip R Lazzara  1 , Amy Lian  1 , Zamia Siddiqui  1 , Thomas E Speltz  2 , Terry W Moore  3
Affiliations
Review

Steroid receptor/coactivator binding inhibitors: An update

Kornelia J Skowron et al. Mol Cell Endocrinol. .

Abstract

The purpose of this review is to highlight recent developments in small molecules and peptides that block the binding of coactivators to steroid receptors. These coactivator binding inhibitors bind at the coregulator binding groove, also known as Activation Function-2, rather than at the ligand-binding site of steroid receptors. Steroid receptors that have been targeted with coactivator binding inhibitors include the androgen receptor, estrogen receptor and progesterone receptor. Coactivator binding inhibitors may be useful in some cases of resistance to currently prescribed therapeutics. The scope of the review includes small-molecule and peptide coactivator binding inhibitors for steroid receptors, with a particular focus on recent compounds that have been assayed in cell-based models.

Keywords: Androgen receptor; Coactivator binding inhibitors; Estrogen receptor; Progesterone receptor; Protein-protein interactions; Steroid receptor coactivator.

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Figures

Figure 1.
Figure 1.
A surface representation of a nuclear receptor. Shown are the ligand-binding domains of three steroid receptors, ligand binding pocket (green), binding function-3 (teal), activation function 2 (beige), and coactivator peptide (brown). (A) The estrogen receptor ligand binding domain (PDB: 5WGD; lilac). (B) The androgen receptor ligand binding domain (PDB: 5JJM; yellow). (C) The progesterone receptor ligand binding domain (PDB: 4OAR; red).
Figure 2.
Figure 2.
A schematic representation of a nuclear receptor. Shown are nuclear receptor ligand binding domain (yellow), ligand binding pocket (green), binding function-3 (blue), activation function 2 (beige), coactivator peptide (brown), and coactivator binding inhibitor (CBI-purple). (A) The coactivator interacts with the nuclear receptor and leads to transcription. (B) The coactivator binding inhibitor prevents coactivator from interacting with nuclear receptor and leads to inhibition of transcription.
Figure 3.
Figure 3.
Small-molecule inhibitors of the estrogen receptor - steroid receptor coactivator interaction.
Figure 4.
Figure 4.
Peptide inhibitors of the estrogen receptor - steroid receptor coactivator interaction.
Figure 5
Figure 5
Small-molecule inhibitors of the androgen receptor - steroid receptor coactivator interaction.
Figure 6.
Figure 6.
Peptide inhibitor of the progesterone receptor-steroid receptor coactivator
See this image and copyright information in PMC

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