ZB716, a steroidal selective estrogen receptor degrader (SERD), is orally efficacious in blocking tumor growth in...

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.