Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer

Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first gener-ation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine -substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clin-ical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent phar-macokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

Automated summary

Although endocrine therapies have shown good responses in ER+ breast cancer patients, drug resistance remains an issue. Researchers developed a new class of orally bioavailable fluorine-substituted SERDs, one of which (27b) shows excellent pharmacokinetic profiles and potential as an orally available SERD for clinical use.