Funding Source

National Institute on Minority Health and Health Disparities, National Institutes of Health, National Cancer Institute

Grant Number

1R43CA213462, 2G12MD007595, CA200517

Department

Department of Chemistry

Document Type

Article

Publication Date

1-8-2018

Abstract

Advances in oral SERDs development so far have been confined to nonsteroidal molecules such as those containing a cinnamic acid moiety, which are in earlystage clinical evaluation. ZB716 was previously reported as an orally bioavailable SERD structurally analogous to fulvestrant. In this study, we examined the binding details of ZB716 to the estrogen receptor alpha (ERα) by computer modeling to reveal its interactions with the ligand binding domain as a steroidal molecule. We also found that ZB716 modulates ERα-coregulator interactions in nearly identical manner to fulvestrant. The ability of ZB716 to inhibit cell growth and downregulate ER expression in endocrine resistant, ERα mutant breast cancer cells was demonstrated. Moreover, in both the MCF-7 xenograft and a patient derived xenograft model, orally administered ZB716 showed superior efficacy in blocking tumor growth when compared to fulvestrant. Importantly, such enhanced efficacy of ZB716 was shown to be attributable to its markedly higher bioavailability, as evidenced in the final plasma and tumor tissue concentrations of ZB716 in mice where drug concentrations were found significantly higher than in the fulvestrant treatment group.

Comments

DOI: 10.18632/oncotarget.24023

Funding text

This study was supported by NIH grants 2G12MD007595 from NIMHD, 1R43CA213462 from NCI, CA200517, and by Louisiana Cancer Research Consortium.

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