The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)
Abstract
The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure–activity relationship (SAR) studies of small-molecule ERα degraders based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have resulted in the discovery of highly potent and effective PROTAC ER degraders, as exemplified by ERD-308 ( 32 ). ERD-308 achieves DC 50 (concentration causing 50% of protein degradation) values of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines, respectively, and induces >95% of ER degradation at concentrations as low as 5 nM in both cell lines. Significantly, ERD-308 induces more complete ER degradation than fulvestrant, the only approved selective ER degrader (SERD), and is more effective in inhibition of cell proliferation than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may lead to a new therapy for advanced ER+ breast cancer.
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Cites
Molecular basis of agonism and antagonism in the oestrogen receptor
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Induced protein degradation: an emerging drug discovery paradigm
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Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
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Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
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PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
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Tamoxifen: a most unlikely pioneering medicine
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The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
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Cited by
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
Burslem, G. M., & Crews, C. M. (2020) · Cell · doi:10.1016/j.cell.2019.11.031 · Cited by 1,079
Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K.-S., Kaniskan, H. Ü., Xiong, Y., & Jin, J. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00365-x · Cited by 632
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 490
Advances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Henley, M. J., & Koehler, A. N. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00199-0 · Cited by 409
Antibody–PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4
Maneiro, M., Forte, N., Shchepinova, M. M., Kounde, C. S., Chudasama, V., Baker, J. R., & Tate, E. W. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00285 · Cited by 350
Metadata
- Authors
- Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C.-Y., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., Delproposto, J., Stuckey, J., & Wang, S.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-01-18
- Volume
- 62
- Issue
- 3
- Pages
- 1420-1442
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2908747386
- Cited by
- 268
- References
- 59
- FWCI
- 10.10
- Type
- journal article
- Language
- en
- Open access
- closed
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- Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C.-Y., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., Delproposto, J., Stuckey, J., & Wang, S. (2019). Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER). Journal of Medicinal Chemistry. https://doi.org/10.1021/acs.jmedchem.8b01572
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