|Other names||ERα coregulator-binding modulator-11|
|Chemical and physical data|
|Molar mass||608.648 g·mol−1|
|3D model (JSmol)|
ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.
ERX-11 is an orally active small-molecule tribenzamide compound which shows good antiestrogenic potency in vitro and minimal indications of toxicity in vivo in animals, even at doses much higher than the therapeutic doses. The compound mimics a nuclear receptor binding motif that appears to be critical for the interaction of the ERα with its coactivators. It is able to disrupt interactions between the ERα and 91 ERα-binding coregulators, including SRC1, SRC3, and PELP1. ERX-11 blocked estradiol-induced proliferation in 8 of 8 ER-positive breast cancer cell lines, with IC50 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. It was inactive in ER-negative breast cancer cell lines.
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. 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%). It also induced apoptosis in breast cancer cells, unlike tamoxifen. Efforts are underway to assess ERX-11 in human clinical trials.
- Raj GV, Sareddy GR, Ma S, Lee TK, Viswanadhapalli S, Li R, Liu X, Murakami S, Chen CC, Lee WR, Mann M, Krishnan SR, Manandhar B, Gonugunta VK, Strand D, Tekmal RR, Ahn JM, Vadlamudi RK (August 2017). "Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers". eLife. 6. doi:10.7554/eLife.26857. PMC 5548489. PMID 28786813.
- Ekoue DN, Unni N, Raj GV (April 2018). "A new class of agents for estrogen-receptor-positive breast cancer". Expert Rev Clin Pharmacol. 11 (4): 325–328. doi:10.1080/17512433.2018.1439736. PMID 29439601.
- Qin, Weirong; Xie, Mingsheng; Qin, Xuan; Fang, Qi; Yin, Feng; Li, Zigang (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. ISSN 0960-894X. PMID 30025900.
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 Chem. Biol. 13 (3): 676–684. doi:10.1021/acschembio.7b01016. PMC 6057476. PMID 29309722.
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.