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 | |
| State | Published - Aug 9 2018 |
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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 journal › Article
}
TY - JOUR
T1 - New Class of Selective Estrogen Receptor Degraders (SERDs)
T2 - Expanding the Toolbox of PROTAC Degrons
AU - Wang, Lucia
AU - Guillen, Valeria S.
AU - Sharma, Naina
AU - Flessa, Kevin
AU - Min, Jian
AU - Carlson, Kathryn E.
AU - Toy, Weiyi
AU - Braqi, Sara
AU - Katzenellenbogen, Benita S
AU - Katzenellenbogen, John A.
AU - Chandarlapaty, Sarat
AU - Sharma, Abhishek
PY - 2018/8/9
Y1 - 2018/8/9
N2 - 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.
AB - 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.
KW - Targeted protein degradation
KW - antagonist
KW - antiproliferation
KW - breast cancer
KW - estrogen receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=85049744230&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.8b00106
DO - 10.1021/acsmedchemlett.8b00106
M3 - Article
VL - 9
SP - 803
EP - 808
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 8
ER -