E74-like factor 3–Mediator complex subunit 23 protein–protein interface (ELF3–MED23 PPI)

The E74-like factor 3 (ELF3, also known as ESX)–Mediator complex subunit 23 (MED23, also known as SUR2) protein–protein interface is a specialized transcriptional regulatory site. ELF3 is an epithelial-restricted ETS-family transcription factor that is frequently overexpressed in early-stage breast cancers (UniProt: P78545). It functions by binding to the promoter of the HER2/ERBB2 oncogene and recruiting the Mediator complex through a direct interaction with the MED23 subunit (Asada et al., 2002, Nature). This recruitment is essential for the high-level transcription of HER2, which drives cell proliferation and survival in HER2-amplified malignancies. Small molecule inhibitors, such as the Wren series (e.g., Wren-1), have been developed to specifically disrupt this interface, leading to decreased HER2 mRNA and protein levels and subsequent growth inhibition in sensitive cancer cell lines (Mapp et al., 2014, ACS Chem. Biol.). Targeting this interface offers a strategy to modulate oncogenic transcription directly, potentially bypassing resistance mechanisms associated with kinase inhibitors. However, because MED23 is a component of the large, multi-subunit Mediator complex involved in many signaling pathways, ensuring the specificity of inhibitors to the ELF3-binding site is a primary safety and therapeutic challenge.

Other names

ESX–Med23 interfaceESX–SUR2 interfaceELF3–SUR2 interactionE74-like factor 3–Mediator complex subunit 23 interaction

Inhibition of the protein-protein interaction between the transcription factor ELF3 (ESX) and the Mediator subunit MED23 (SUR2), thereby preventing the recruitment of the Mediator complex to the HER2 promoter and reducing oncogene expression.