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

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.

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“…A glide tool (Friesner et al, 2006) was used for docking of the fulvestrant. Since the structures of fulvestrant and ZB716 are similar, the same protocol using a flexible docking simulation was performed with the Induced Fit protocol (IFD) method as previously reported (Guo et al, 2018). The docking complexes were refined with the protein-ligand interaction refinement tool in the Schrödinger suite.…”

Metabolism, pharmacokinetics, and bioavailability of ZB716, a Steroidal Selective Estrogen Receptor Downregulator (SERD)

“…In both tamoxifen naive and tamoxifen resistant breast cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose-dependent manner. In mice, we have shown that ZB716 has far superior oral bioavailability when compared to fulvestrant [ 27 – 28 ], and in two breast cancer xenograft models including a patient derived xenograft (PDX) model, ZB716 has proven to be a more efficacious SERD than fulvestrant in inhibiting tumor growth [ 28 ].…”

“…The only structural difference between ZB716 and fulvestrant is that the 3-hydroxyl group of fulvestrant is replaced by a boronic acid moiety in ZB716 [ 27 ]. The single substitution of -OH with –B(OH) 2 (Figure 1 ) is apparently responsible for the vastly improved oral bioavailability while retaining potent biological activities of ZB716 as compared to fulvestrant [ 27 – 28 ]. In mice and rats, oral administration of ZB716 at 10 mg/kg afforded peak plasma concentrations in excess of 100 ng/mL, a level significantly higher than the 20 ng/mL observed for fulvestrant administered at similar dosage via s.c. injection in animals [ 27 – 28 ].…”

“…The single substitution of -OH with –B(OH) 2 (Figure 1 ) is apparently responsible for the vastly improved oral bioavailability while retaining potent biological activities of ZB716 as compared to fulvestrant [ 27 – 28 ]. In mice and rats, oral administration of ZB716 at 10 mg/kg afforded peak plasma concentrations in excess of 100 ng/mL, a level significantly higher than the 20 ng/mL observed for fulvestrant administered at similar dosage via s.c. injection in animals [ 27 – 28 ]. Such superior oral bioavailability of ZB716 was translated to greater efficacy in blocking tumor growth in xenograft models [ 28 ].…”

“…In mice and rats, oral administration of ZB716 at 10 mg/kg afforded peak plasma concentrations in excess of 100 ng/mL, a level significantly higher than the 20 ng/mL observed for fulvestrant administered at similar dosage via s.c. injection in animals [ 27 – 28 ]. Such superior oral bioavailability of ZB716 was translated to greater efficacy in blocking tumor growth in xenograft models [ 28 ]. However, it is not fully understood how the substitution of the phenolic OH group with a boronic acid structure leads to such dramatic enhancement of oral bioavailability as seen in ZB716.…”