Protacs Targeting ERα in the Effective Management of Endocrinal Resistance Breast Cancer

Abstract

The estrogen receptor is a central mediator of estrogen-driven gene expression, influencing a wide array of physiological processes. Conventional endocrine therapies, including selective estrogen receptor modulators (SERMs) and degraders (SERDs), often face limitations due to acquired resistance and reduced efficacy in ERα-mutant cancers. Proteolysis-targeting chimeras (PROTACs) serve as a next-generation therapeutic strategy designed to selectively and efficiently degrade estrogen receptor alpha (ERα). The approval of elacestrant further expanded interest in developing novel ERα degraders, shifting the paradigm of drug discovery in this area. This review highlights the mechanism of action of PROTACs, structural and functional domains of ERα, design of PROTACs, and their application in targeting the ERα receptor. Special emphasis is also given on structure activity relationship (SAR) studies and strategies of designing PROTACs reported in the literature, along with in vitro and in vivo studies data. Collectively, these strategies provide valuable insights for designing effective PROTACs to overcome endocrine resistance and advance therapeutic options in ERα-positive breast cancers.