Nonsteroidal estrogen receptor modulators (SERM) emerge as one promising avenue. These compounds bind to estrogen receptors, blocking certain hormones that can accelerate tumor growth. Moreover, recognizing the potential of this mechanism, researchers have focused on Bazedoxifene (TSE-424), a nonsteroidal estrogen receptor modulator. Bazedoxifene has been approved in Europe as a monotherapy for the prevention of osteoporosis, as well as in the US in combination with conjugated estrogens. Structurally distinct from other drugs like Raloxifene and Tamoxifen, Bazedoxifene creates more steric hindrance towards helix 12. Besides, it binds to estrogen receptors (ER) with high affinity, acting as a potent antagonist inhibiting E2-induced proliferation in MCF7 cells. In addition, Bazedoxifene shows activity even in Tamoxifen-resistant xenografts, demonstrating its antiestrogenic properties, not solely reliant on ER degradation.

Bazedoxifene is an oral, BBB-penetrant nonsteroidal selective estrogen receptor modulator against cancer.

In vitro, Bazedoxifene, a small molecular GP130 inhibitor, specifically binds to the GP130 D1 domain. It plays a crucial role in inhibiting STAT3 phosphorylation, which is induced by Il-6 and IL-11 in the GP130/STAT3 pathway signaling. When applied to human pancreatic cancer cells at 10 μM-20 μM for two hours, Bazedoxifene effectively inhibits cytokines-induced STAT3 phosphorylation. Moreover, with an overnight treatment using Bazedoxifene at 5-20 μM, apoptosis is induced in these cancer cells. Additionally, Bazedoxifene inhibits IL-6 induced STAT3 nuclear translocation and arrests cell migration in pancreatic cancer cells through the inhibition of GP130.

In preclinical animal models, Bazedoxifene (5 mg/kg; Oral gavage; daily, for 18 days) inhibits Capan-1 tumor growth in mouse model. Bazedoxifene suppresses pancreatic cancer xenograft tumor growth and induced apoptosis in tumor cells.

In conclusion, Bazedoxifene is an orally active and BBB-penetrant nonsteroidal estrogen receptor modulator. With its potent anticancer activity shown both in vitro and in vivo, it brings us a step closer to a new class of targeted therapies.


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[3] Xiaojuan Wu, et al. Mol Cancer Ther. 2016 Nov; 15(11): 2609–2619.