Novel Selective Inhibitors of the Interaction of Individual Nuclear Hormone Receptors with a Mutually Shared Steroid Receptor Coactivator 2

Nuclear hormone receptor (NR) signaling, currently a therapeutic target in multiple diseases, involves an ordered series of protein interactions to regulate transcription in response to changing hormone levels. Later steps in the process of ligand-dependent signaling are driven by a highly conserved interaction between the NRs and the steroid receptor coactivators (SRCs) that is effected by a conserved interaction motif (L1XXL2L3), known as an NR box. Using computational design and combinatorial chemistry, we have produced novel α-helical proteomimetics of the second NR box of SRC2 that exploit structural differences between human estrogen receptor α (hERα), human estrogen receptor β (hERβ), and human thyroid hormone receptor β (hTRβ). The resulting library sequentially replaced each leucine with non-natural side chains. Screening this library using a quantitative competition assay revealed compounds that selectively inhibit the interaction of SRC2-2 with each individual NR in preference to its interaction with the other NR. This approach generated highly selective compounds from one that had no specificity for a particular family member. These compounds represent the first family-member-selective competitive inhibitors of the protein interactions of transcription factors.