While therapy of estrogen receptor alpha positive (ERα+) breast cancer is often initially successful with ERα modulating or inhibiting drugs, eventual drug resistance is universal and such treatments are rarely curative. To address this considerable medical need, several generations of novel anti-tumor small molecule agents specifically targeting the estrogen-ERα interaction have been synthesized and characterized. We are pursuing an alternative approach, activation of an endogenous cell death pathway downstream of ERα with non-competitive Selective Estrogen Receptor Activators (SERAs). These compounds exhibit their effects by dysregulating calcium homeostasis in ERα+ tumor cells leading to hyper-activation of the anticipatory unfolded protein response (a-UPR) and necrotic cell death, a mechanism distinct from current breast cancer therapeutics. These molecules cause increases in P-EIF2a and P-AMPK, and cleavage of ATF6α, which are all hallmarks of the hyper-activation of a-UPR. SERA molecules cause death of ERα+ breast cancer cells in culture with 24hr IC₅₀ values in the low nanomolar range, including breast cancer cell lines harboring ERα mutations known to contribute to acquired ERα modulator therapy resistance, while IC₅₀ values in ERα-negative cells are orders of magnitude higher. In the MCF-7 ERα+ breast cancer xenograft model, once weekly IV injections of SERA2 at 10mg/kg cause durable, complete tumor regression, and SERA2 also has impressive activity in a challenging-to-treat PDX model that is resistant to fulvestrant and tamoxifen. SERAs are well-tolerated after multiple intravenous injections in mice, rats, and dogs, and clinical trial-compatible formulations have been developed. These findings suggest that SERA molecules can address the important unmet clinical need for more effective therapies for patients with ERα+ tumors who progress on conventional SERM, SERD, and targeted therapies.

Citation Format: Michael P. Mulligan, Matthew W. Boudreau, David J. Shapiro, Timothy M. Fan, Paul J. Hergenrother, Kerry Barnhart, David Azorsa, Jeff Kiefer, Spyro Mousses. Selective estrogen receptor a-UPR activators (SERA): a novel class of small molecules that eradicate estrogen receptor positive tumors . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 522

References:

1. Boudreau, M.; et al. “A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice”. Sci. Transl. Med. 2021, 13 (603), eabf1383.

2. Boudreau, M.; Mulligan, M.; et al. “Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer”. J. Med. Chem. 2022, 65, 3894-3912.

3. Boudrea, M. et al. “Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity”. RSC Med. Chem. 2022, 13, 711–725.

4. Uddin, M.; et al. “Syntheses and antiproliferative evaluation of oxyphenisatin derivatives”. Bioorg. Med. Chem. Lett. 2007, 17, 2854–2857.

5. Natarajan, A.; et al. “3,3-Diaryl-1,3-dihydroindol-2-ones as Antiproliferatives Mediated by Translation Initiation Inhibition”. J. Med. Chem. 2004, 47, 1882-1885.

6. Christensen, M.; et al. “Synthesis and Antitumor Effect in Vitro and in Vivo of Substituted 1,3-Dihydroindole-2-ones”. J. Med. Chem. 2010, 53, 19, 7140–7145.

7. Shapiro, D. et al. “Anticipatory UPR Activation: A Protective Pathway and Target in Cancer” Trends Endocrinol. Metab. 2016, 10, 731