期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 9, 期 8, 页码 803-808出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00106
关键词
Targeted protein degradation; estrogen receptor; antiproliferation; breast cancer; antagonist
资金
- Stevens Institute of Technology
- NIH [R01DK015556, T32GM070421]
- NCI Cancer Center Support Grant [P30CA08748]
- Breast Cancer Research Foundation [BCRF 17-083, BCRF 17-082, BCRF 17-185]
- NATIONAL CANCER INSTITUTE [R01CA204999, P30CA008748] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK015556] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM070421] Funding Source: NIH RePORTER
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.
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