ERX-11 is an orally activesmall-moleculetribenzamide compound which shows good antiestrogenic potencyin vitro and minimal indications of toxicityin vivo in animals, even at doses much higher than the therapeutic doses.[1][2] The compound mimics a nuclear receptorbinding motif that appears to be critical for the interaction of the ERα with its coactivators.[1][2] It is able to disrupt interactions between the ERα and 91 ERα-binding coregulators, including SRC1Tooltip steroid receptor coactivator 1, SRC3Tooltip steroid receptor coactivator 3, and PELP1Tooltip proline-, glutamic acid- and leucine-rich protein 1.[1][2] ERX-11 blocked estradiol-induced proliferation in 8 of 8 ER-positive breast cancer cell lines, with IC50Tooltip half-maximal inhibitory concentration values ranging between 250 nM and 500 nM, and was as effective as tamoxifen and fulvestrant in inhibiting the growth of the ZR-75 and MCF-7 breast cancer cell lines.[1][2] It was inactive in ER-negative breast cancer cell lines.[1][2]
In contrast to conventional antiestrogens like tamoxifen and fulvestrant, ERX-11 was found to block both ligand-dependent and ligand-independent ER signaling as well as ER signaling in both therapy-sensitive and therapy-resistant breast cancer cells.[1][2] In addition, it disrupted interactions between the ERα and many ERα-binding coregulators not affected by conventional antiestrogens like tamoxifen (33 of 88 proteins, or 37.5%).[1][2] It also induced apoptosis in breast cancer cells, unlike tamoxifen.[1][2] Efforts are underway to assess ERX-11 in human clinical trials.[2]
^Qin W, Xie M, Qin X, Fang Q, Yin F, Li Z (September 2018). "Recent advances in peptidomimetics antagonists targeting estrogen receptor α-coactivator interaction in cancer therapy". Bioorganic & Medicinal Chemistry Letters. 28 (17): 2827–2836. doi:10.1016/j.bmcl.2018.05.062. PMID30025900. S2CID51702195. In 2017, Raj et al. reported a small molecule compound 12, which was the most well-characterized small molecule for inhibiting ERα-coactivator interaction.50 Compound 12 is a tri-benzamide that could inhibit the proliferation of several different ERα-positive breast cancer cells. Notably, it could regress the growth of ERα-positive breast cancer xenograft in vivo. 12 was designed to bind to the coactivator binding groove of ERα, but the mode of action and precise binding site were not fully elucidated yet.
^Speltz TE, Danes JM, Stender JD, Frasor J, Moore TW (March 2018). "A Cell-Permeable Stapled Peptide Inhibitor of the Estrogen Receptor/Coactivator Interaction". ACS Chemical Biology. 13 (3): 676–684. doi:10.1021/acschembio.7b01016. PMC6057476. PMID29309722. The most well-characterized molecule for inhibiting the ER/coregulator interaction comes from Raj et al., who recently described ERX-11, a small molecule that is active in several different models of ER+ breast cancer, including a tumor xenograft model.18 ERX-11 is an oligoamide that was designed to bind to ER at the coregulator-binding region, but even after careful experimentation and design, the precise binding site and mode of action is not fully understood for ERX-11, demonstrating the difficult nature of designing inhibitors of this protein−protein interaction.
