Breast Cancer Research and Treatment

, Volume 133, Issue 1, pp 99–109 | Cite as

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

  • Wenjie Jessie Lu
  • Cong Xu
  • Zifan Pei
  • Abdelrahman S. Mayhoub
  • Mark Cushman
  • David A. Flockhart
Preclinical study


To improve the treatment of breast cancer, there has been a need for alternative aromatase inhibitors (AIs) that bring about adequate aromatase inhibition, while limiting side effects. Since two tamoxifen metabolites have been documented as AIs, we tested a wide range of tamoxifen metabolites on aromatase in order to better understand structural interactions with aromatase and constructed structure–function relationships as a first step toward the development of novel inhibitors. The ability of ten tamoxifen metabolites to inhibit recombinant aromatase (CYP19) was tested using microsomal incubations. The selectivity of the most potent aromatase inhibitor identified, norendoxifen, was characterized by studying its ability to inhibit CYP450 enzymes important in clinical drug–drug interactions, including CYP2B6, 2C9, 2C19, 2D6, and 3A. Computerized molecular docking with the X-ray crystallographic structure of aromatase was used to describe the detailed biochemical interactions involved. The inhibitory potency order of the tested compounds was as follows: norendoxifen ≫ 4,4′-dihydroxy-tamoxifen > endoxifen > N-desmethyl-tamoxifen, N-desmethyl-4′-hydroxy-tamoxifen, tamoxifen-N-oxide, 4′-hydroxy-tamoxifen, N-desmethyl-droloxifene > 4-hydroxy-tamoxifen, tamoxifen. Norendoxifen inhibited recombinant aromatase via a competitive mechanism with a K i of 35 nM. Norendoxifen inhibited placental aromatase with an IC50 of 90 nM, while it inhibited human liver CYP2C9 and CYP3A with IC50 values of 990 and 908 nM, respectively. Inhibition of human liver CYP2C19 by norendoxifen appeared even weaker. No substantial inhibition of CYP2B6 and CYP2D6 by norendoxifen was observed. These data suggest that multiple metabolites of tamoxifen may contribute to its action in the treatment of breast cancer via aromatase inhibition. Most of all, norendoxifen may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents. The range of structures tested in this study and their pharmacologic potencies provide a reasonable pharmacophore upon which to build novel AIs.


Breast cancer Tamoxifen Endoxifen Norendoxifen Aromatase inhibitor Estrogen 





Aromatase inhibitor.


Selective estrogen receptor modulator






High-performance liquid chromatography


Human liver microsomes


Cytochrome P450






The half maximal inhibitory concentration


The equilibrium dissociation constant of the inhibitor



This work was supported in part by the National Institutes of Health National Center for Research Resources [Grant K24RR020815] to DAF, by the National Institute for General Medical Sciences [Grants T32GM008425, U01GM061373] to DAF, by a Department of Defense Breast Cancer Research Program Predoctoral Fellowship [W81XWH-11-1-0016] to WJL and by a fellowship to ASM from the Egyptian government.

Conflicts of interest

WJL and DAF are authors of a patent submitted to the US patent office that describes new uses of the chemical structures described herein entitled ‘‘Materials for inhibiting aromatase and method of using the same to diagnose, treat and monitor breast cancer’’. Other authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Wenjie Jessie Lu
    • 1
  • Cong Xu
    • 1
  • Zifan Pei
    • 2
  • Abdelrahman S. Mayhoub
    • 3
  • Mark Cushman
    • 3
  • David A. Flockhart
    • 1
  1. 1.Division of Clinical Pharmacology, Department of Pharmacology and ToxicologyIndiana University Simon Cancer Center, Indiana University School of MedicineIndianapolisUSA
  2. 2.Department of Pharmacology and ToxicologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and The Purdue Center for Cancer ResearchPurdue UniversityWest LafayetteUSA

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