The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs). (27th October 2020)

• Record Type: Journal Article
• Authors: Wang, Lucia; Sharma, Abhishek
• Is Part Of: ChemMedChem. Volume 15:Number 22(2020)
• Page Start: 2072
• Page End: 2097
• Publication Date: 2020-10-27
• Subjects: anti-tumor agents -- cancer -- drug design -- medicinal chemistry -- structure-activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000473
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 Abstract : Something easier to swallow : Selective estrogen receptor degraders (SERDs) represent the last line of treatment for resistant metastatic estrogen receptor‐alpha (ERα)‐positive breast cancer. The only clinically approved SERD, Fulvestrant, presents a poor pharmacokinetic profile which limits its overall clinical benefit. This review summarizes recent efforts towards orally available SERDs.