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Cited by 28Estrogen and related hormone effectsProtein Degradation and InhibitorsAdvanced Breast Cancer Therapies

Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer

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Wang, Yubo, Min, Jian, Deng, Xiangping, Feng, Tian, Hu, Hebing, Guo, Xinyi, Cheng, Yan, Xie, Baohua +5 more·2023·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2023.05.005PMC PMC10692362
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Abstract

Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα+) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα+ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

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  • Targeting ERα signaling is widely regarded as the most effective therapeutic strategy for ERα-positive breast cancer, such as Tamoxifen, Fulvestrant, and Letrozole, which have brought significant prognostic improvements for ER+ breast cancer.

    “Targeting ERα signaling is widely regarded as the most effective therapeutic strategy for ERα-positive breast cancer, such as Tamoxifen, Fulvestrant, and Letrozole, which have brought significant prognostic improvements for ER+ breast cancer52.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [52]

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  1. [1]Siegel R.L. Miller K.D. Jemal A. Cancer statistics Ca - Cancer J Clin 70 2020 7 30 2020 31912902
  2. [2]Tong C.W.S. Wu M. Cho W.C.S. To K.K.W. Recent advances in the treatment of breast cancer Front Oncol 8 2018 227 29963498 PMC6010518
  3. [3]Anderson W.F. Katki H.A. Rosenberg P.S. Incidence of breast cancer in the United States: current and future trends J Natl Cancer Inst 103 2011 1397 1402 21753181 PMC3176776
  4. [4]Eckhardt B.L. Francis P.A. Parker B.S. Anderson R.L. Strategies for the discovery and development of therapies for metastatic breast cancer Nat Rev Drug Discov 11 2012 479 497 22653217
  5. [6]Gandhi N. Das G.M. Metabolic reprogramming in breast cancer and its therapeutic implications Cells 8 2019 89 30691108 PMC6406734
  6. [7]Ciruelos E. Pascual T. Arroyo Vozmediano M.L. Blanco M. Manso L. Parrilla L. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer Breast 23 2014 201 208 24589524
  7. [8]Lin X. Xiang H. Luo G. Targeting estrogen receptor α for degradation with PROTACs: a promising approach to overcome endocrine resistance Eur J Med Chem 206 2020 112689 32829249
  8. [10]Lai A. Kahraman M. Govek S. Nagasawa J. Bonnefous C. Julien J. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts J Med Chem 58 2015 4888 4904 25879485
  9. [11]Hu J. Hu B. Wang M. Xu F. Miao B. Yang C.Y. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER) J Med Chem 62 2019 1420 1442 30990042
  10. [12]Lu Z. Cao Y. Zhang D. Meng X. Guo B. Kong D. Discovery of thieno[2,3-e]indazole derivatives as novel oral selective estrogen receptor degraders with highly improved antitumor effect and favorable druggability J Med Chem 65 2022 5724 5750 35357160
  11. [13]Lai A.C. Crews C.M. Induced protein degradation: an emerging drug discovery paradigm Nat Rev Drug Discov 16 2017 101 114 27885283 PMC5684876
  12. [14]Robertson J.F.R. Bondarenko I.M. Trishkina E. Dvorkin M. Panasci L. Manikhas A. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial Lancet 388 2016 2997 3005 27908454
  13. [15]Howell A. Sapunar F. Fulvestrant revisited: efficacy and safety of the 500-mg dose Clin Breast Cancer 11 2011 204 210 21729658
  14. [17]Hernando C. Ortega-Morillo B. Tapia M. Moragón S. Martínez M.T. Eroles P. Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective Int J Mol Sci 22 2021 7812 34360578 PMC8345926
  15. [18]Fanning S.W. Mayne C.G. Dharmarajan V. Carlson K.E. Martin T.A. Novick S.J. Estrogen receptor α somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation Elife 5 2016 e12792 PMC4821807 26836308
  16. [19]Wang L. Sharma A. The quest for orally available selective estrogen receptor degraders (SERDs) ChemMedChem 15 2020 2072 2097 32916035
  17. [20]Kiely-Collins H. Winter G.E. Bernardes G.J.L. The role of reversible and irreversible covalent chemistry in targeted protein degradation Cell Chem Biol 28 2021 952 968 33789091
  18. [21]Abdeldayem A. Raouf Y.S. Constantinescu S.N. Moriggl R. Gunning P.T. Advances in covalent kinase inhibitors Chem Soc Rev 49 2020 2617 2687 32227030
  19. [23]De Vita E. 10 years into the resurgence of covalent drugs Future Med Chem 13 2021 193 210 33275063 PMC8356679
  20. [24]Boike L. Henning N.J. Nomura D.K. Advances in covalent drug discovery Nat Rev Drug Discov 2022 1 18 36008483 PMC9403961
  21. [25]Furman C. Hao M.H. Prajapati S. Reynolds D. Rimkunas V. Zheng G.Z. Estrogen receptor covalent antagonists: the best is yet to come Cancer Res 79 2019 1740 1745 30952631
  22. [26]Furman C. Puyang X. Zhang Z. Wu Z.J. Banka D. Aithal K.B. Covalent ERα antagonist H3B-6545 demonstrates encouraging preclinical activity in therapy-resistant breast cancer Mol Cancer Therapeut 21 2022 890 902 PMC9381127 35642432
  23. [27]Puyang X. Furman C. Zheng G.Z. Wu Z.J. Banka D. Aithal K. Discovery of selective estrogen receptor covalent antagonists for the treatment of ERαWT and ERαMUT breast cancer Cancer Discov 8 2018 1176 1193 29991605
  24. [29]Zhou H.B. Comninos J.S. Stossi F. Katzenellenbogen B.S. Katzenellenbogen J.A. Synthesis and evaluation of estrogen receptor ligands with bridged oxabicyclic cores containing a diarylethene motif: estrogen antagonists of unusual structure J Med Chem 48 2005 7261 7274 16279785
  25. [30]Ning W. Hu Z. Tang C. Yang L. Zhang S. Dong C. Novel hybrid conjugates with dual suppression of estrogenic and inflammatory activities display significantly improved potency against breast cancer J Med Chem 61 2018 8155 8173 30053783
  26. [31]Tang C. Li C. Zhang S. Hu Z. Wu J. Dong C. Novel bioactive hybrid compound dual targeting estrogen receptor and histone deacetylase for the treatment of breast cancer J Med Chem 58 2015 4550 4572 25993269
  27. [33]Aliau S. Mattras H. Richard E. Borgna J.L. Cysteine 530 of the human estrogen receptor alpha is the main covalent attachment site of 11β-(aziridinylalkoxyphenyl)estradiols Biochemistry 38 1999 14752 14762 10555957
  28. [34]Katzenellenbogen J.A. The 2010 Philip S. Portoghese medicinal chemistry lectureship: addressing the "core issue" in the design of estrogen receptor ligands J Med Chem 54 2011 5271 5282 21707083 PMC3150643
  29. [35]Weerapana E. Wang C. Simon G.M. Richter F. Khare S. Dillon M.B. Quantitative reactivity profiling predicts functional cysteines in proteomes Nature 468 2010 790 795 21085121 PMC3058684
  30. [36]Nacht M. Qiao L. Sheets M.P. St Martin T. Labenski M. Mazdiyasni H. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3K α. J Med Chem 56 2013 712 721 23360348
  31. [37]Hu Z. Li Y. Xie B. Ning W. Xiao Y. Huang Y. Novel class of 7-oxabicyclo[2.2.1]heptene sulfonamides with long alkyl chains displaying improved estrogen receptor α degradation activity Eur J Med Chem 182 2019 111605 31437778
  32. [38]Li Y. Zhang S. Zhang J. Hu Z. Xiao Y. Huang J. Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs) Eur J Med Chem 172 2019 48 61 30939353
  33. [39]Zheng Y. Zhu M. Srinivasan S. Nwachukwu J.C. Cavett V. Min J. Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands ChemMedChem 7 2012 1094 1100 22517684 PMC4301955
  34. [40]Srinivasan S. Nwachukwu J.C. Bruno N.E. Dharmarajan V. Goswami D. Kastrati I. Full antagonism of the estrogen receptor without a prototypical ligand side chain Nat Chem Biol 13 2017 111 118 27870835 PMC5161551
  35. [41]Fanning S.W. Jeselsohn R. Dharmarajan V. Mayne C.G. Karimi M. Buchwalter G. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells Elife 7 2018 e37161 PMC6335054 30489256
  36. [42]Wang C. Li C. Zhou H. Huang J. High-throughput screening assays for estrogen receptor by using coumestrol, a natural fluorescence compound J Biomol Screen 19 2014 253 258 24019253
  37. [43]Min J. Nwachukwu J.C. Min C.K. Njeri J.W. Srinivasan S. Rangarajan E.S. Dual-mechanism estrogen receptor inhibitors Proc Natl Acad Sci U S A 118 2021 e2101657118 PMC8536401 34452998

Cited by

Sorted by citations

Authors
Wang, Y., Min, J., Deng, X., Feng, T., Hu, H., Guo, X., Cheng, Y., Xie, B., Yang, Y., Chen, C.-C., Guo, R.-T., Dong, C., & Zhou, H.-B.
Affiliations
  • Wuhan University (CN)
  • State Key Laboratory of Biocatalysis and Enzyme Engineering (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
  • Guo, Rey-Ting
  • Dong, Chune
  • Zhou, Hai-Bing
ORCID
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2023-12
Volume
13
Issue
12
Pages
4963-4982
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2023.05.005
PMC
PMC10692362
OpenAlex
W4382311091
Cited by
28
References
5
Citations by year
2026: 9 · 2025: 12 · 2024: 6 · 2023: 1
FWCI
4.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key Research and Development Program of China (2020YFA0908800, 2021YFC2100300)
  • Fundamental Research Funds for the Central Universities (2042022kf0056)
  • China Postdoctoral Science Foundation (2020M672435)
  • National Natural Science Foundation of China (81773557, 82073690, 82103994, 82173676, 82273774)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
Keywords
endocrine therapy resistance, estrogen receptor alpha, breast cancer, protein degradation, hydrophobic interactions, crystal structure, MCF-7 xenografts, anticancer activity, fulvestrant

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