GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer

Abstract

Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug−drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1 Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021

“…It is worth noting that two of the presented molecules, i.e., adavosertib (formerly AZD1775 ) and pemrametostat (formerly GSK3326595 ), are characterized by a completely new mechanism of action, such as WEE1 G2 checkpoint kinase (WEE1) inhibition and protein arginine methyltransferase 5 (PRMT5) inhibition, respectively [ 271 , 272 ]. The next two agents, i.e., ARV-471 and giredestrant (also known as GDC-9545 ) are specifically designed to target and degrade the estrogen receptor (ER) during the treatment of patients with breast cancer [ 273 , 274 ]. It should be emphasized that ARV-471 is one of the first clinically evaluated proteolysis-targeting chimera (PROTAC) molecules.…”

Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

“…As mentioned above, fulvestrant is the only approved SERD for the therapy of postmenopausal aBC patients to date. However, since there is a lack of oral bioavailability of fulvestrant, therefore requiring intramuscular injection of it [ 83 , 84 ], other novel SERDs with the potential of oral bioavailability are being investigated [ 85 , 86 , 87 , 88 , 89 ] ( Table 2 ). A first-in-human study on the SERD AZD9496, for instance, showed an acceptable safety profile and a prolongation of disease stabilization in women with hormone-receptor-positive aBC [ 90 ], but its preoperative influence on estrogen receptor expression was not superior to fulvestrant within a recent window of an opportunity trial in eBC [ 91 ].…”

A New Era in ER+ Breast Cancer: Best-in-Class Oral Selective Estrogen Receptor Degrader (SERD) Designed as an Endocrine Backbone Treatment

“…The superior potency was the result of extensive optimization of antagonist and degradation potencies and a relentless focus on achieving the best ligand-lipophilicity efficiency. 3,4 The superior potencies of GDC-9545, coupled with its excellent oral exposure, translate into excellent in vivo efficacies either as a single agent or in combination with a CDK4/6 inhibitor. The projected human efficacious dose is ∼1 mg once per day, targeting tumor regression in the PDX tumor model which harbors an ESR1 mutation.…”

“…The exact reason why a clinical candidate was terminated is often not published. The featured article by Liang et al in this issue of the Journal of Medicinal Chemistry sheds light toward this as the authors disclose their third generation clinical candidate GDC-9545 (giredestrant) …”