ERX-11
Chemical compound / From Wikipedia, the free encyclopedia
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.[1][2] 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.[1][2] 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.[1][2][3][4] Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.[1]
Clinical data | |
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Other names | ERα coregulator-binding modulator-11 |
Routes of administration | By mouth[1][2] |
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Chemical and physical data | |
Formula | C31H36N4O9 |
Molar mass | 608.648 g·mol−1 |
3D model (JSmol) | |
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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.[1][2] The compound mimics a nuclear receptor binding 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]