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

doi:10.1021/acsmedchemlett.8b00106

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

Molecular and Integrative Physiology

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	803-808
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00106
State	Published - Aug 9 2018

Keywords

Targeted protein degradation
antagonist
antiproliferation
breast cancer
estrogen receptor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.8b00106

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Wang, L., Guillen, V. S., Sharma, N., Flessa, K., Min, J., Carlson, K. E., Toy, W., Braqi, S., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Chandarlapaty, S., & Sharma, A. (2018). New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons. ACS Medicinal Chemistry Letters, 9(8), 803-808. https://doi.org/10.1021/acsmedchemlett.8b00106

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 journal › Article › peer-review

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

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.",

keywords = "Targeted protein degradation, antagonist, antiproliferation, breast cancer, estrogen receptor",

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

note = "Funding Information: We thank Dr. Athula Attygalle for HRMS analysis and Ye Zheng for assistance in some experiments. Financial support from Stevens Institute of Technology (to A.S.), the NIH (R01DK015556 to J.A.K.; predoctoral fellowship T32GM070421 to V.S.G.), NCI Cancer Center Support Grant (P30CA08748) to MSKCC, and the Breast Cancer Research Foundation (BCRF 17-083 to J.A.K. and B.S.K.; BCRF 17-082 to B.S.K.; BCRF 17-185 to S.C.) is gratefully acknowledged.",

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AU - Flessa, Kevin

AU - Min, Jian

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AU - Toy, Weiyi

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AU - Katzenellenbogen, John A.

AU - Chandarlapaty, Sarat

AU - Sharma, Abhishek

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