Marcus Russell

Background: Estrogen receptor positive/human epidermal growth factor receptor-2 negative (ER-positive/HER2-negative) breast cancer, accounts for 65-75% of breast cancers^1,2. This subtype of breast cancer has a 50% risk of recurrence within 5 years, with an ongoing risk past 10 years^1,2. Growth of this cancer is mediated by estrogen receptor alpha (ERα), which when bound to estrogen will dimerize and translocate to the nucleus, where it will complex with various coactivators (CoA) to become transcriptionally active³. Current therapies that attempt to target the estrogen-estrogen receptor axis include aromatase inhibitors, selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs)^1,2,3. These endocrine therapies are susceptible to mutations in the ligand binding domain (LBD) of ERα e.g. Y537S and D538G that cause the receptor to become constitutively active^3,4. The need for a drug that could maintain efficacy despite the presence of these mutations led to the development of a new class of drug: selective estrogen receptor covalent antagonists (SERCAs)⁵.

Objective: In this review, the development and mechanism of SERCAs, their efficacy in inhibiting tumor growth, and their progress through preclinical studies and into clinical trials is discussed.

Search Methods: All research was done through the online PubMed database using the MeSH terms “breast neoplasm,” “estrogen receptor alpha,” “estrogen receptor antagonists,” and “selective estrogen receptor modulators” from the years 2018-2024.

Results: In the study that discovered SERCAs, it was shown that the drug H3B-5942 could bind covalently to a C530 in the LBD of ERα through a Michael addition reaction, in which the drug acts as the alpha/beta unsaturated Michael acceptor⁵. This reaction caused ERα to shift into an antagonistic conformation⁵. In this study, H3B-5942 showed inhibition of CoA recruitment and downstream ERα gene expression, antiproliferative effects in breast cancer cell lines, and inhibition of tumor growth in mice xenografted with a patient derived tumor expressing the Y537S mutation⁵. H3B-5942 showed a strong dependence on covalent binding due to the reduced efficacy of its saturated analogue⁵. This led to the development of H3B-6545, which has greater stability and can maintain efficacy when bound to ERα noncovalently⁶. H3B-6545 showed inhibition of tumor growth in mice xenografted with wild type, Y537S-mutant, and palbociclib resistant tumors, with stronger efficacy compared to standard of care (SoC) endocrine therapies⁶. The success of H3B-6545 in this study led to further characterization of its metabolic and pharmacokinetic profile by another study, which estimated that it would have a 7-8hr half life in a healthy adult female⁷. Two other studies synthesized new SERCAs using raloxifene, a SERM, and two benzothiophene scaffolds^8,9. These studies showed the importance of the Michael addition reaction, and created compounds with stronger efficacy compared to SoC endocrine therapies^8,9. H3B-6545 was evaluated in patients with metastatic and therapy-resistant breast cancer, where it showed antitumor activity¹⁰. It is currently being evaluated in two additional clinical trials^11,12.

Conclusion: The discovery of SERCAs may allow for a new therapeutic approach to ER-positive/HER2-negative breast cancer. A drug within this class, H3B-6545, showed efficacy in preclinical studies and is currently being evaluated in clinical trials, while other studies are being done to discover additional drugs within this class.

Works Cited:

1. Huppert LA, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023;73(5):480-515. doi:10.3322/caac.21777
2. Burstein HJ. Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer. N Engl J Med. 2020;383(26):2557-2570. doi:10.1056/NEJMra1307118
3. Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell. 2020;37(4):496-513. doi:10.1016/j.ccell.2020.03.009
4. Gates LA, Gu G, Chen Y, et al. Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets. Oncogene. 2018;37(33):4581-4598. doi:10.1038/s41388-018-0284-2
5. Puyang X, Furman C, Zheng GZ, et al. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov. 2018;8(9):1176-1193. doi:10.1158/2159-8290.CD-17-1229
6. Furman C, Puyang X, Zhang Z, et al. Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer. Mol Cancer Ther. 2022;21(6):890-902. doi:10.1158/1535-7163.MCT-21-0378
7. Rioux N, Smith S, Korpal M, et al. Nonclinical pharmacokinetics and in vitro metabolism of H3B-6545, a novel selective ERα covalent antagonist (SERCA). Cancer Chemother Pharmacol. 2019;83(1):151-160. doi:10.1007/s00280-018-3716-3
8. Bai C, Ren S, Wu S, Zhu M, Luo G, Xiang H. Design and synthesis of novel benzothiophene analogs as selective estrogen receptor covalent antagonists against breast cancer. Eur J Med Chem. 2021;221:113543. doi:10.1016/j.ejmech.2021.113543
9. Bai C, Lv Y, Xiong S, et al. X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles. Bioorg Chem. 2023;141:106919. doi:10.1016/j.bioorg.2023.106919
10. Hamilton EP, Wang JS, Pluard TJ, et al. Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. J Clin Oncol. 2021;39(15_suppl):1018-1018. doi:10.1200/JCO.2021.39.15_suppl.1018
11. Eisai Co., Ltd. A Phase 1 Study of H3B-6545 in Japanese Women With Estrogen Receptor-Positive, HER2 Negative Breast Cancer. clinicaltrials.gov; 2023. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT04568902
12. Eisai Inc. An Open-Label Multicenter Phase 1b Study of H3B-6545 in Combination With Palbociclib in Women With Advanced or Metastatic Estrogen Receptor-Positive HER2-Negative Breast Cancer. clinicaltrials.gov; 2024. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT04288089