GDC-6599

GDC-6599 (also known as RG6795) is an investigational, orally bioavailable proteolysis-targeting chimera (PROTAC) developed by Genentech for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The molecule is designed to selectively target the estrogen receptor alpha (ERα) and recruit an E3 ubiquitin ligase, leading to the ubiquitination and subsequent degradation of the receptor via the proteasome. By degrading the ER protein rather than simply blocking it, GDC-6599 aims to achieve more robust inhibition of ER signaling and potentially overcome resistance mechanisms, such as ESR1 mutations, that often limit the efficacy of standard-of-care endocrine therapies like aromatase inhibitors or selective estrogen receptor modulators (SERMs). It is currently being evaluated in Phase 1 clinical trials as a monotherapy and in combination with other targeted agents.