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, <b>35</b> (GDC-9545 or giredestrant). <b>35</b> is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (<b>1</b>, <b>6</b>, <b>7</b>, and <b>9</b>) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of <b>35</b> in preclinical species and humans. <b>35</b> exhibits low drug-drug interaction liability and demonstrates excellent <i>in vitro</i> and <i>in vivo</i> safety profiles. At low doses, <b>35</b> induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1<sup>Y537S</sup> mutant PDX or a wild-type ERα tumor model. Currently, <b>35</b> is being evaluated in Phase III clinical trials.