Breast cancer is the most common malignant tumor in women worldwide, and estrogen receptor (ER)α-positive breast cancer accounts for about 70%. To date, the primary intervention for the treatment of ERα-positive breast cancer is traditional endocrine therapy, but the problem of drug resistance caused by this treatment remains a major obstacle to long-term treatment of breast cancer. In order to overcome this disadvantage, oral estrogen receptor degraders and emerging protein degrading drug technologies have been developed. This review will focus on the latest research progress of targeted ERα degradation drugs, so as to provide reference for the subsequent development of drugs for the treatment of ERα-positive breast cancer.

1.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

2.Do Nascimento RG, Otoni KM. Histological and molecular classification of breast cancer: what do we know?[J]. Mastology, 2020, 30: e20200024. DOI: 10.29289/25945394202020200024.

3.Akram M, Iqbal M, Daniyal M, et al. Awareness and current knowledge of breast cancer[J]. Biol Res, 2017, 50(1): 33. DOI: 10.1186/s40659-017-0140-9.

4.刘宇婷, 刘鷖雯, 何怡青, 等. 雌激素受体相关信号通路在乳腺癌内分泌治疗耐药中的研究进展[J]. 医学研究杂志, 2024, 53(9): 7-11. [Liu YT, Liu YW, He YQ, et al. Research progress of estrogen receptor-related signaling pathway in breast cancer resistance to endocrine therapy[J]. Journal of Medical Research, 2019, 53(9): 7-11.] DOI: 10.11969/j.issn.1673-548X.2024.09.002.

5.Paterni I, Granchi C, Katzenellenbogen JA, et al. Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential[J]. Steroids, 2014, 90: 13-29. DOI: 10.1016/j.steroids.2014.06.012.

6.Yaşar P, Ayaz G, User SD, et al. Molecular mechanism of estrogen-estrogen receptor signaling[J]. Reprod Med Biol, 2016, 16(1): 4-20. DOI: 10.1002/rmb2.12006.

7.Garcia-Martinez L, Zhang Y, Nakata Y, et al. Epigenetic mechanisms in breast cancer therapy and resistance[J]. Nat Commun, 2021, 12(1): 1786. DOI: 10.1038/s41467-021-22024-3.

8.Patel R, Klein P, Tiersten A, et al. An emerging generation of endocrine therapies in breast cancer: a clinical perspective[J]. NPJ Breast Cancer, 2023, 9(1): 20. DOI: 10.1038/s41523-023-00523-4.

9.Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies[J]. Future Med Chem, 2015, 7(12): 1511-1519. DOI: 10.4155/fmc.15.93.

10.Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment[J]. Pharmacol Ther, 2018, 186: 1-24. DOI: 10.1016/j.pharmthera.2017.12.012.

11.Iorfida M, Mazza M, Munzone E. Fulvestrant in combination with CDK4/6 Inhibitors for HER2- metastatic breast cancers: current perspectives[J]. Breast Cancer (Dove Med Press), 2020, 12: 45-56. DOI: 10.2147/BCTT.S196240.

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

13.Neupane N, Bawek S, Gurusinghe S, et al. Oral SERD, a novel endocrine therapy for estrogen receptor-positive breast cancer[J]. Cancers (Basel), 2024, 16(3): 619. DOI: 10.3390/cancers16030619.

14.Varella L, Cristofanilli M. Evaluating elacestrant in the management of ER-positive, HER2-negative advanced breast cancer: evidence to date[J]. Onco Targets Ther, 2023, 16: 189-196. DOI: 10.2147/OTT.S400563.

15.Wardell SE, Nelson ER, Chao CA, et al. Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader[J]. Endocr Relat Cancer, 2015, 22(5): 713-724. DOI: 10.1530/ERC-15-0287.

16.Bardia A, Kaklamani V, Wilks S, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer[J]. J Clin Oncol, 2021, 39(12): 1360-1370. DOI: 10.1200/JCO.20.02272.

17.Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial[J]. J Clin Oncol, 2022, 40(28): 3246-3256. DOI: 10.1200/JCO.22.00338.

18.Elgene L, Komal LJ, Jose APF, et al. A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer[J]. J Clin Oncol, 2020, 38: 1023-1023. DOI: 10.1200/JCO.2020.38.15_suppl.1023.

19.Miguel M, Elgene L, Mariana CMG, et al. AcelERA breast cancer (BC): phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician's choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC)[J]. J Clin Oncol, 2021, 39(15_suppl): TPS1100-TPS1100. DOI: 10.1200/JCO.2021.39.15_suppl.TPS1100.

20.Qureshi Z, Jamil A, Altaf F, et al. Elacestrant in the treatment landscape of ER-positive, HER2-negative, ESR1-mutated advanced breast cancer: a contemporary narrative review[J]. Ann Med Surg (Lond), 2024, 86(8): 4624-4633. DOI: 10.1097/MS9.0000000000002293.

21.Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue[J]. Nat Rev Drug Discov, 2022, 21(3): 181-200. DOI: 10.1038/s41573-021-00371-6.

22.Dang CV, Reddy EP, Shokat KM, et al. Drugging the 'undruggable' cancer targets[J]. Nat Rev Cancer, 2017, 17(8): 502-508. DOI: 10.1038/nrc.2017.36.

23.Han X, Sun Y. PROTACs: a novel strategy for cancer drug discovery and development[J]. MedComm (2020), 2023, 4(3): e290. DOI: 10.1002/mco2.290.

24.Qi SM, Dong J, Xu ZY, et al. PROTAC: an effective targeted protein degradation strategy for cancer therapy[J]. Front Pharmacol, 2021, 12: 692574. DOI: 10.3389/fphar.2021.692574.

25.ARV-471: Phase 2 VERITAC trial results-Arvinas[EB/OL]. (2024-08-30) [2024-10-18]. https://ir.arvinas.com/static-files/e0d56eb4-13c4-43e9-935d-f24a18d2fe6e.

26.Hamilton EP, Ma C, De Laurentiis M, et al. VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2-advanced breast cancer[J]. Future Oncol, 2024, 20(32): 2447-2455. DOI: 10.1080/14796694.2024.2377530.

27.Chen Z, Hu B, Rej RK, et al. Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity[J]. J Med Chem, 2023, 66(17): 12559-12585. DOI: 10.1021/acs.jmedchem.3c01186.

28.Rej RK, Allu SR, Roy J, et al. Orally bioavailable proteolysis-targeting chimeras: an innovative approach in the golden era of discovering small-molecule cancer drugs[J]. Pharmaceuticals (Basel), 2024, 17(4): 494. DOI: 10.3390/ph17040494.

29.Chen Z, Hu B, Rej RK, et al. Discovery of ERD-3111 as a potent and orally efficacious estrogen receptor PROTAC degrader with strong antitumor activity[J]. J Med Chem, 2023, 66(17): 12559-12585. DOI: 10.1021/acs.jmedchem.3c01186.

30.Liu J, Ma J, Liu Y, et al. PROTACs: a novel strategy for cancer therapy[J]. Semin Cancer Biol, 2020, 67(Pt 2): 171-179. DOI: 10.1016/j.semcancer.2020.02.006.

31.Zeng S, Huang W, Zheng X, et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges[J]. Eur J Med Chem, 2021, 210: 112981. DOI: 10.1016/j.ejmech.2020.112981.

32.Hu B, Hu J. Complete elimination of estrogen receptor α by PROTAC estrogen receptor α degrader ERD-148 in breast cancer cells[J]. Breast Cancer Res Treat, 2024, 203(2): 383-396. DOI: 10.1007/s10549-023-07136-2.

33.Gonzalez TL, Hancock M, Sun S, et al. Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer[J]. Breast Cancer Res Treat, 2020, 180(3): 611-622. DOI: 10.1007/s10549-020-05564-y.

34.Roberts BL, Ma ZX, Gao A, et al. Two-stage strategy for development of proteolysis targeting chimeras and its application for estrogen receptor degraders[J]. ACS Chem Biol, 2020, 15(6): 1487-1496. DOI: 10.1021/acschembio.0c00140.

35.Wang C, Zhang Y, Shi L, et al. Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents[J]. J Enzyme Inhib Med Chem, 2022, 37(1): 1437-1453. DOI: 10.1080/14756366.2022.2074414.

36.Itoh Y, Kitaguchi R, Ishikawa M, et al. Design, synthesis and biological evaluation of nuclear receptor-degradation inducers[J]. Bioorg Med Chem, 2011, 19(22): 6768-6778. DOI: 10.1016/j.bmc.2011.09.041.

37.Demizu Y, Okuhira K, Motoi H, et al. Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy[J]. Bioorg Med Chem Lett, 2012, 22(4): 1793-1796. DOI: 10.1016/j.bmcl.2011.11.086.

38.Ohoka N. Development of protein knockdown technology as emerging drug discovery strategy[J]. Yakugaku Zasshi. 2018, 138(9): 1135-1143. DOI: 10.1248/yakushi.18-00113.

39.Yokoo H, Ohoka N, Takyo M, et al. Peptide stapling improves the sustainability of a peptide-based chimeric molecule that induces targeted protein degradation[J]. Int J Mol Sci, 2021, 22(16): 8772. DOI: 10.3390/ijms22168772.

40.Han X, Sun Y. Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy[J]. Cell Rep Phys Sci, 2022, 3(10): 101062. DOI: 10.1016/j.xcrp.2022.101062.

41.He W, Zhang H, Perkins L, et al. Abstract PS18-09: novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant[J]. Cancer Res, 2021, 81(4_Supplement): PS18-09. https://DOI.org/10.1158/1538-7445.SABCS20-PS18-09.

42.Li J, Chen X, Lu A, et al. Targeted protein degradation in cancers: Orthodox PROTACs and beyond[J]. Innovation (Camb), 2023, 4(3): 100413. DOI: 10.1016/j.xinn.2023.100413.

43.Rej RK, Thomas JE 2nd, Acharyya RK, et al. Targeting the estrogen receptor for the treatment of breast cancer: recent advances and challenges[J]. J Med Chem, 2023, 66(13): 8339-8381. DOI: 10.1021/acs.jmedchem.3c00136.

44.Wang Z, Che S, Yu Z. PROTAC: Novel degradable approach for different targets to treat breast cancer[J]. Eur J Pharm Sci, 2024, 198: 106793. DOI: 10.1016/j.ejps.2024.106793.

45.Kaur R, Chaudhary G, Kaur A, et al. PROTACs: a hope for breast cancer patients?[J]. Anticancer Agents Med Chem, 2022, 22(3): 406-417. DOI: 10.2174/1871520621666210308100327.

46.李永正, 张静娟, 宋健, 等. 蛋白降解靶向纳米嵌合体在肿瘤治疗中的应用进展[J]. 中国医学前沿杂志(电子版), 2024, 16(10): 26-34. [Li YZ, Zhang JJ, Song J, et al. Targeted protein degradation of the progress in the application of nano chimeras in tumor therapy[J]. Chinese Journal of the Frontiers of Medical Science (Electronic Version), 2024, 16(10): 26-34.] DOI: 10.12037/YXQY.2024.10-04.