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
N1 - 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.
Publisher Copyright:
© 2018 American Chemical Society.
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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U2 - 10.1021/acsmedchemlett.8b00106
DO - 10.1021/acsmedchemlett.8b00106
M3 - Article
C2 - 30128071
AN - SCOPUS:85049744230
VL - 9
SP - 803
EP - 808
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 8
ER -