New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons

作者：Wang Lucia; Guillen Valeria S; Sharma Naina; Flessa Kevin; Min Jian; Carlson Kathryn E; Toy Weiyi; Braqi Sara; Katzenellenbogen Benita S; Katzenellenbogen John A; Chandarlapaty Sarat; Sharma Abhishek^*

来源：ACS Medicinal Chemistry Letters, 2018, 9(8): 803-808.

DOI：10.1021/acsmedchemlett.8b00106

• Targeted protein degradation
• estrogen receptor
• antiproliferation
• breast cancer
• antagonist

An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.

• 出版日期2018-8