Boronic Prodrug of 4-hydroxytamoxifen is more Efficacious than Tamoxifen with Enhanced Bioavailability Independent of CYP2D*6 Status

Funding Source

National Institutes of Health

Grant Number

G12MD007595, U54GM104940


Department of Chemistry

Document Type


Publication Date



Background: Poor initial response to tamoxifen due to CYP2D*6*4-OHT at therapeutically effective concentrations but at a fraction of the standard tamoxifen dose. Methods: A mouse xenograft tumor model was used to investigate the efficacy of ZB497 in comparison with tamoxifen. Pharmacokinetic studies were conducted to evaluate the metabolism and bioavailability of the drug in mice. Drug and metabolites distribution in xenograft tumor tissues was determined by high performance liquid chromatography-tandem mass spectrometry. Results: The boronic prodrug, ZB497, can not only be efficiently converted to 4-OHT in mice, but also afforded over 30 fold higher plasma concentrations of 4-OHT than in mice given either the same dose of 4-OHT or tamoxifen. Further, ZB497 was more effective than tamoxifen at lowered dosage in inhibiting the growth of xenograft tumors in mice. Consistent with these observations, ZB497 treated mice accumulated over 6 times higher total drug concentrations than tamoxifen treated mice. Conclusions: Our study demonstrates that ZB497 effectively delivers a markedly increased plasma concentration of 4-OHT in mice. The boronic prodrug was shown to have far superior bioavailability of 4-OHT compared to tamoxifen or 4-OHT administration as measured by the area under the plasma concentration time curve (AUC), plasma peak concentrations, and drug accumulation in tumor tissues. Further, ZB497 proves to be a more efficacious hormone therapy than tamoxifen administered at a reduced dose in mice.


DOI: 10.1186/s12885-015-1621-2

PubMed ID: 26354796