Discovery of non-antiproliferative selective estrogen receptor degraders (SERDs) based on scaffold optimization of elacestrant

  • Eur J Med Chem. 2024 Dec 5:279:116897. doi: 10.1016/j.ejmech.2024.116897.
Yunlong Lu  1 ,  Zhihao Zhao  2 ,  Shanglong Wang  2 ,  Tianpeng Zheng  2 ,  Xuejie Chen  2 ,  Lijuan Liu  2 ,  Yuqing Zhu  2 ,  Wukun Liu  3
Affiliations
  • 1. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
  • 2. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
PMID: 39353239 DOI: 10.1016/j.ejmech.2024.116897
Abstract

Elacestrant, the first oral selective Estrogen receptor Degrader (SERD), has been approved for ER positive breast Cancer in 2023. Recent study showed that elacestrant has moderate pharmacokinetic property and the oral bioavailability is 11 %. In this study, we have performed docking analyses of elacestrant with different Cytochrome P450 isoforms. The results indicated that tetrahydronaphthalene scaffold of elacestrant located closely to Heme iron center of P450s and might undergo rapid metabolism by CYP3A4. Therefore, we have changed the tertiary carbon atom to nitrogen atom of the scaffold to attenuate the metabolic effect. The most interesting finding is that compound B16 exhibited significant degradation of ERα at 5 μM but didn't show antiproliferative activity at high concentrations in MCF-7 and T47D cells. Compound B16 may serve as an ER probe to investigate ER status in ER positive breast Cancer cells.

Keywords
Breast cancer; Elacestrant; Estrogen receptor; Oral SERD.
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