Discovery and Development of a Highly Potent, Orally Bioavailable Estrogen Receptor Full Antagonist and Degrader: Giredestrant (GDC-9545) for Estrogen Receptor-Positive Breast Cancer

We describe the discovery and development of a highly-potent, orally-bioavailable estrogen receptor full antagonist and degrader – giredestrant (GDC-9545) as a treatment for estrogen receptor-positive breast cancer. After a brief introduction on breast cancer and a rationale for targeting the estrogen receptor, an overview of the medicinal chemistry effort that led to the discovery of giredestrant and our initial medicinal chemistry route is presented. Subsequently, we provide details of how an efficient manufacturing route was developed to support mid- and late-stage clinical trials.