Optimization of Small Molecule Degraders and Antagonists for Targeting Estrogen Receptor Based on Breast Cancer: Current Status and Future

Overview

Journal Front Pharmacol

Date 2023 Oct 9

PMID 37808197

Authors

Jiaqi Yao

Yiran Tao

Zelin Hu

Junjie Li

Ziyi Xue

Ya Zhang

Yi Lei

Affiliations

Soon will be listed here.

Abstract

The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.

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References

Wang Y, Tang S . The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options. Cancer Metastasis Rev. 2022; 41(4):975-990. PMC: 9560885. DOI: 10.1007/s10555-022-10066-y. View

Maguire P, Margolin S, Skoglund J, Sun X, Gustafsson J, Borresen-Dale A . Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer. Breast Cancer Res Treat. 2005; 94(2):145-52. DOI: 10.1007/s10549-005-7697-7. View

Baker M . Insights from the structure of estrogen receptor into the evolution of estrogens: implications for endocrine disruption. Biochem Pharmacol. 2011; 82(1):1-8. DOI: 10.1016/j.bcp.2011.03.008. View

Khosla S, Oursler M, Monroe D . Estrogen and the skeleton. Trends Endocrinol Metab. 2012; 23(11):576-81. PMC: 3424385. DOI: 10.1016/j.tem.2012.03.008. View

Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P . Breast cancer. Nat Rev Dis Primers. 2019; 5(1):66. DOI: 10.1038/s41572-019-0111-2. View

Reinbolt R, Mangini N, Hill J, Levine L, Dempsey J, Singaravelu J . Endocrine therapy in breast cancer: the neoadjuvant, adjuvant, and metastatic approach. Semin Oncol Nurs. 2015; 31(2):146-55. DOI: 10.1016/j.soncn.2015.02.002. View

Brett J, Spring L, Bardia A, Wander S . ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021; 23(1):85. PMC: 8365900. DOI: 10.1186/s13058-021-01462-3. View

Zbieg J, Liang J, Li J, Blake R, Chang J, Friedman L . Discovery of GNE-502 as an orally bioavailable and potent degrader for estrogen receptor positive breast cancer. Bioorg Med Chem Lett. 2021; 50:128335. DOI: 10.1016/j.bmcl.2021.128335. View

Baraka A, Korish A, Soliman G, Kamal H . The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease. Life Sci. 2011; 88(19-20):879-85. DOI: 10.1016/j.lfs.2011.03.010. View

10.

Tria G, Abrams T, Baird J, Burks H, Firestone B, Gaither L . Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer. J Med Chem. 2018; 61(7):2837-2864. DOI: 10.1021/acs.jmedchem.7b01682. View

11.

Liu H, Liu J, van Breemen R, Thatcher G, Bolton J . Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4'-fluoro substitution prevents quinoid formation. Chem Res Toxicol. 2005; 18(2):162-73. DOI: 10.1021/tx049776u. View

12.

Ladd B, Mazzola A, Bihani T, Lai Z, Bradford J, Collins M . Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations. Oncotarget. 2016; 7(34):54120-54136. PMC: 5342331. DOI: 10.18632/oncotarget.10852. View

13.

Guo S, Zhang C, Mottamal M, Hossain A, Liu J, Wang G . GLL398, an oral selective estrogen receptor degrader (SERD), blocks tumor growth in xenograft breast cancer models. Breast Cancer Res Treat. 2020; 180(2):359-368. PMC: 7069796. DOI: 10.1007/s10549-020-05558-w. View

14.

Zhang M, Liu Z, Aoshima K, Cai W, Sun H, Xu T . CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Sci Transl Med. 2022; 14(630):eabf5473. PMC: 9003667. DOI: 10.1126/scitranslmed.abf5473. View

15.

Chau C, Steeg P, Figg W . Antibody-drug conjugates for cancer. Lancet. 2019; 394(10200):793-804. DOI: 10.1016/S0140-6736(19)31774-X. View

16.

Bogliolo S, Cassani C, Dominoni M, Orlandini A, Ferrero S, Iacobone A . The role of fulvestrant in endometrial cancer. Expert Opin Drug Metab Toxicol. 2016; 13(5):537-544. DOI: 10.1080/17425255.2016.1244264. View

17.

Jhaveri K, Juric D, Yap Y, Cresta S, Layman R, Duhoux F . A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2021; 27(21):5760-5770. PMC: 9401512. DOI: 10.1158/1078-0432.CCR-21-1095. View

18.

Harlow K, Smith D, Katzenellenbogen J, Greene G, Katzenellenbogen B . Identification of cysteine 530 as the covalent attachment site of an affinity-labeling estrogen (ketononestrol aziridine) and antiestrogen (tamoxifen aziridine) in the human estrogen receptor. J Biol Chem. 1989; 264(29):17476-85. View

19.

Puyang X, Furman C, Zheng G, Wu Z, Banka D, Aithal K . Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα and ERα Breast Cancer. Cancer Discov. 2018; 8(9):1176-1193. DOI: 10.1158/2159-8290.CD-17-1229. View

20.

El-Ahmad Y, Tabart M, Halley F, Certal V, Thompson F, Filoche-Romme B . Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of.... J Med Chem. 2019; 63(2):512-528. DOI: 10.1021/acs.jmedchem.9b01293. View