Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα).

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC value of 47 pM and is 10 times more potent than ARV-471.

Attempted replication of pharmacogenetic association of variants in PPP1R14C and CCDC148 with aromatase inhibitor-induced musculoskeletal symptoms.

Third-generation aromatase inhibitors (AI) are the standard treatment for patients with hormone receptor positive (HR+) breast cancer. While effective, AI can lead to severe adverse events, including AI-induced musculoskeletal syndrome (AIMSS). Genetic predictors of AIMSS have the potential to personalize AI treatment and improve outcomes.

Discovery of as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with being the most promising compound.

Effects of and genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226.

This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, (rs11648166) and (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Participants in the anastrozole-only arm with low CYP3A4 activity (i.e.