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| Other names | ERα coregulator-binding modulator-11 |
| Routes of administration | By mouth[1][2] |
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| Formula | C31H36N4O9 |
| Molar mass | 608.648 g·mol−1 |
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ERX-11, also known asERα coregulator-binding modulator-11, is a novelantiestrogen andexperimentalhormonal antineoplastic agent which is being researched for the potential treatment ofestrogen receptor-positivebreast cancer.[1][2] It is not acompetitiveantagonist of theestrogen receptor (ER) like conventional antiestrogens such astamoxifen orfulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of theERα and blocksprotein–protein interactions of the ERα withcoregulators that are necessary for thereceptor to act and regulategene expression.[1][2] It was designed to bind to the coregulatorbinding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site andmode of action have yet to be fully elucidated and understood.[1][2][3][4] Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.[1]
ERX-11 is anorally activesmall-moleculetribenzamide compound which shows good antiestrogenicpotencyin vitro and minimal indications oftoxicityin vivo in animals, even at doses much higher than the therapeutic doses.[1][2] The compound mimics anuclear 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, includingSRC1Tooltip steroid receptor coactivator 1,SRC3Tooltip steroid receptor coactivator 3, andPELP1Tooltip proline-, glutamic acid- and leucine-rich protein 1.[1][2] ERX-11 blocked estradiol-inducedproliferation in 8 of 8 ER-positive breast cancercell lines, withIC50Tooltip 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 theZR-75 andMCF-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 inducedapoptosis in breast cancer cells, unlike tamoxifen.[1][2] Efforts are underway to assess ERX-11 in humanclinical trials.[2]
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.
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.
