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Imlunestrant
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What is the mechanism of action of imlunestrant?
Imlunestrant is a potent, orally bioavailable selective estrogen receptor degrader with pure antagonistic properties resulting in sustained inhibition of estrogen receptor-dependent gene transcription and cell growth.
Mechanism of Action (MOA)
Imlunestrant is a potent degrader and selective pure antagonist of wild-type and mutant estrogen receptor alpha (ERα). In cell proliferation assays, it selectively inhibits the proliferation of estrogen receptor-positive (ER+) breast cancer cell lines and has equivalent potency in both wild-type and mutant estrogen receptor gene (ESR1) cell lines. In the in-vivo target inhibition studies, imlunestrant has shown sustained and prolonged inhibition of expression of progesterone receptor (PgR), a transcriptional target of ERα and a pharmacodynamic biomarker in ESR1 wild-type and ESR1 (Y537S)-mutant xenograft or patient-derived xenograft (PDX) tumor models in mice. In in vivo efficacy studies, imlunestrant has demonstrated robust single agent activity and tumor regressions in ESR1 wild-type (MCF7, T47D, ZR-75-1, HCC1428) xenograft models and ESR1-mutant (Y537S, E380Q) PDX models. In preclinical combination efficacy studies, imlunestrant has shown good tolerability and enhanced efficacy with abemaciclib, alpelisib, and everolimus.1-4
Figure 1 description: The selective estrogen receptor degradation mechanism of action of imlunestrant is illustrated. Imlunestrant has demonstrated inhibition of estrogen-dependent signaling and subsequent inhibition of cell proliferation in estrogen receptor wild-type and mutant expressing tumor models.
Abbreviation: ER = estrogen receptor.
Additional information on the MOA of imlunestrant is available in the imlunestrant MOA video.
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Bhagwat SV, Zhao B, Shen W, et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD). Cancer Res. 2021;81(13 suppl):1236. American Association for Cancer Research abstract 1236. https://doi.org/10.1158/1538-7445.AM2021-1236
2Bhagwat SV, Zhao B, Shen W, et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD). Poster presented at: 112th Annual Meeting of the American Association for Cancer Research (AACR Virtual); April 10-15, May 17-21, 2021.
3Vandekopple M, Mur C, Shen W, et al. Preclinical characterization of imlunestrant, an oral brain-penetrant selective estrogen receptor degrader with activity in a brain metastasis (BM) model. ESMO Open. 2023;8(1 suppl 4):101265. European Society for Medical Oncology abstract 41P. https://doi.org/10.1016/j.esmoop.2023.101265
4Vandekopple M, Mur C, Shen W, et al. Preclinical characterization of imlunestrant, an oral brain-penetrant selective estrogen receptor degrader with activity in a brain metastasis (BM) model. Poster presented at: 5th European Society for Medical Oncology Breast Cancer (ESMO-BC) Congress; May 11-13, 2023; Berlin, Germany. Accessed October 11, 2023. https://cslide.ctimeetingtech.com/breast23hybrid/public/download_uploaded_media/pdf/125
5Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1-24. https://doi.org/10.1016/j.pharmthera.2017.12.012
6Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20(7):1757-1767. https://doi.org/10.1158/1078-0432.ccr-13-2332
7Tecalco-Cruz AC, Pérez-Alvarado IA, Ramírez-Jarquín JO, Rocha-Zavaleta L. Nucleo-cytoplasmic transport of estrogen receptor alpha in breast cancer cells. Cell Signal. 2017;34:121-132. https://doi.org/10.1016/j.cellsig.2017.03.011
Date of Last Review: October 02, 2024