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

Lucia Wang, Valeria S. Guillen, Naina Sharma, Kevin Flessa, Jian Min, Kathryn E. Carlson, Weiyi Toy, Sara Braqi, Benita S Katzenellenbogen, John A. Katzenellenbogen, Sarat Chandarlapaty, Abhishek Sharma

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)803-808
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume9
Issue number8
DOIs
StatePublished - Aug 9 2018

Fingerprint

Estrogen Receptors
Scaffolds
Proteins
Breast Neoplasms
Pharmacokinetics
Cell proliferation
Libraries
Genes
Cell Proliferation
Availability
Degradation
fulvestrant

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

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

In: ACS Medicinal Chemistry Letters, Vol. 9, No. 8, 09.08.2018, p. 803-808.

Research output: Contribution to journalArticle

Wang, L, Guillen, VS, Sharma, N, Flessa, K, Min, J, Carlson, KE, Toy, W, Braqi, S, Katzenellenbogen, BS, Katzenellenbogen, JA, Chandarlapaty, S & Sharma, A 2018, 'New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons', ACS Medicinal Chemistry Letters, vol. 9, no. 8, pp. 803-808. https://doi.org/10.1021/acsmedchemlett.8b00106
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. / New Class of Selective Estrogen Receptor Degraders (SERDs) : Expanding the Toolbox of PROTAC Degrons. In: ACS Medicinal Chemistry Letters. 2018 ; Vol. 9, No. 8. pp. 803-808.
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