Targeting the Nuclear Receptor-Cofactor Interaction

Nuclear Receptors as Drug Targets. Edited by Eckhard Ottow and Hilmar Weinmann Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31872-8 

Two major issues have to be dealt with in the search for such types of coactivator binding inhibitors (CBIs) [9]. First of all it has to be proven whether direct inhibition of this interaction is a valid principle to antagonize nuclear receptor functioning. Apart from via the AF-2, nuclear receptors also control gene transcription via their activation function 1 (AF-1), located at the N-terminus of the protein, in a more or less ligand-independent way. This additional interaction actually results in more complex 

In this chapter we discuss both the insight that has been gained concerning the biological relevance of inhibiting the nuclear receptor-coactivator interaction and the progress made in the development of inhibitors for this interaction. The biological 

Evaluation of the Nuclear Receptor-Cofactor Interaction as a Drug Target 

100-fold molar excess of the peptides was required to inhibit SRCla binding by 50%, suggesting that whereas the nuclear receptor box region is a primary site of interaction between SRCla and ER, additional contacts between the coactivator and the ligand-receptor-DNA complex, such as two LXXLL motifs of the same protein binding to the nuclear receptor dimer, and the interaction with the AF-1, contribute to the overall affinity. 

---

The nuclear receptor-cofactor interaction, more specifically the nuclear receptor-coactivator interaction, has emerged as a drugable protein-protein interaction. Even though many aspects of its drugability are still unsolved, both the results obtained on the biological evaluation of its direct inhibition and the development of the first small-molecule inhibitors show the potential of targeting this interaction. 

A field which is still far from being completely understood on a molecular level is the nuclear receptor-cofactor interaction. Luc Brunsveld, B. Vaz and S. Moddinghoff give an introduction to our current knowledge in this field and explain why these interactions might be attractive targets for more selective modulators. 

However, some receptors are constitutively expressed in the nucleus and this type of receptor would not be amenable to a nuclear translocation assay. The activities of nuclear receptors may be dependent upon complex interactions with a number of coregulatory proteins, commonly known as coactivators or corepressors, and modifications by post-translational means. Cell type-specific expression levels of receptors and coregulators may contribute to some, but not all, of the molecular bases for gene and functional selectivity of receptor activity. Therefore selecting a cell line that expresses both the target receptor and the necessary cofactors may be required to design an appropriate assay. 

---