Discovery of Novel Selective Estrogen Receptor β (SERβ) Agonist (S)-STO021 as an Antiosteoporosis Candidate with Dual Functions of Inhibiting Osteoclastogenesis and Activating Osteoblastogenesis

  • J Med Chem. 2025 Nov 13;68(21):22715-22737. doi: 10.1021/acs.jmedchem.5c01697.
Cheng Peng  1 ,  Zixiang Geng  2 ,  Zhe Jiang  1 ,  Jin-Feng Ning  1 ,  Nan Wang  1 ,  Chen Zhong  1 ,  Yongfang Zhao  2 ,  Xun Sun  1  3 ,  Mei-Lin Tang  1  4
Affiliations
  • 1. Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2. Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3. The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China.
  • 4. Shanghai Pudong Hospital, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai 201203, China.
PMID: 41105705 DOI: 10.1021/acs.jmedchem.5c01697
Abstract

Osteoporosis is a systemic and chronic metabolic bone disease of high fracture and mortality. Simultaneous regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption has become a potentially effective therapeutic strategy to overcome osteoporosis. Recently, selective activation of Estrogen receptor β (SERβ) was demonstrated to promote osteoblast formation and inhibit osteoclast absorption, suggesting that SERβ agonists may be another promising therapeutic approach for treating osteoporosis. Herein, we reported the discovery of a bisphosphonate indanone compound (S)-STO021 as a novel SERβ agonist, which exhibited excellent dual functional effects of inhibiting osteoclast resorption and promoting osteoblast formation. Mechanically, the antiosteoporosis efficacy of (S)-STO021 was achieved through inhibiting the TAK1/MKK6/p38 signal and promoting the ERβ/BMP4/SMAD signal. Furthermore, (S)-STO021 could not only effectively improve the zebrafish osteoporosis model induced by glucocorticoids but also greatly restore the bone microstructure in ovariectomized rat models. Collectively, our SERβ agonist (S)-STO021 could regulate osteoblast and osteoclast differentiation, showing the potential to treat osteoporosis.

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