The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70 % of ERα-positive breast cancers. Selective Estrogen Receptor degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast Cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogues of GW5638, an acrylic acid-based ERα ligand developed by Glaxo Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds.

anti-tumor agents; cancer; drug design; medicinal chemistry; structure-activity relationships.