Like fulvestrant, and displaying some improvements over GDC-0927, GDC-9545 consistently induces ER turnover and drives deep transcriptional suppression of ER, resulting in robust in vitro anti-proliferative activity. GDC-9545 is a non-steroidal ER ligand that is highly potent in competing with estradiol for binding and in driving an antagonist conformation within the ER ligand binding domain. Here, we describe for the first time GDC-9545, in which the distinct liabilities of GDC-0810, GDC-0927 and fulvestrant are addressed. Although displaying a more desirable mechanistic profile than GDC-0810, GDC-0927 has more rapid clearance and poor oral bioavailability, leading to a high pill burden and potential exposure limitation. In HCI-011 (ER.WT) and HCI-013 (ER.Y537S) ER+ patient-derived breast cancer xenograft (PDX) models, GDC-0927 achieves more robust transcriptional suppression of ER than GDC-0810, and also and greater efficacy.

GDC-0810, GDC-0927, and fulvestrant display unique profiles in terms of ER degradation, transcriptional phenotypes and anti-proliferative potential across a panel of ER+ breast cancer cell lines. However, we find that therapeutic candidates that have recently emerged from prospective optimization of ER degradation, including GDC-0810 and GDC-0927, are not mechanistically equivalent.

Strategies to generate orally bioavailable molecules that retain fulvestrant's full antagonist profile but with considerably improved drug-like properties are thus being widely employed to identify next generation ER therapeutics. However, the full clinical potential of fulvestrant is believed to be limited by poor physiochemical properties and exposure limitations due to its administration by intramuscular injection. Fulvestrant is unique amongst currently approved ER ligand therapeutics due to its classification as a full ER antagonist, which is thought to be achieved through degradation of ERα protein. ER+ breast cancers depend on ER signaling throughout disease progression, including after acquired resistance to existing endocrine agents, providing a rationale for further optimization and development of ER-targeting agents.

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