Name: ERD-308
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Solubility

10 mM in DMSO

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

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Room temperature in continental US; may vary elsewhere

Synonyms

ERD-308; ERD 308; ERD308; (2S,4R)-1-[(2S)-2-[[2-[5-[ethyl-[2-[4-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophene-3-carbonyl]phenoxy]ethyl]amino]pentoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

InChI Key

BQXUPNKLZNSUMC-YUQWMIPFSA-N

InChI

InChI=1S/C55H65N5O9S2/c1-7-59(26-28-69-43-22-17-37(18-23-43)49(65)48-44-24-21-41(62)30-46(44)71-51(48)39-15-19-40(61)20-16-39)25-9-8-10-27-68-32-47(64)58-52(55(4,5)6)54(67)60-31-42(63)29-45(60)53(66)57-34(2)36-11-13-38(14-12-36)50-35(3)56-33-70-50/h11-24,30,33-34,42,45,52,61-63H,7-10,25-29,31-32H2,1-6H3,(H,57,66)(H,58,64)/t34-,42+,45-,52+/m0/s1

SMILES

CCN(CCCCCOCC(=O)NC(C(=O)N1CC(CC1C(=O)NC(C)C2=CC=C(C=C2)C3=C(N=CS3)C)O)C(C)(C)C)CCOC4=CC=C(C=C4)C(=O)C5=C(SC6=C5C=CC(=C6)O)C7=CC=C(C=C7)O

Mechanism

Target: ERD-308 selectively targets estrogen receptor alpha in ER-positive cellular models.

Binding site: Its ER ligand binds the estrogen receptor ligand-binding domain.

Mechanism of action: ERD-308 is a VHL-recruiting estrogen receptor PROTAC designed to induce potent degradation of ERα. It combines an ERα-binding ligand with a von Hippel-Lindau E3 ligase ligand, allowing ERα to be recruited into proximity with VHL-containing ubiquitination machinery. This ternary-complex-driven process promotes ERα ubiquitination and proteasome-dependent depletion, reducing receptor abundance and downstream estrogen-responsive transcriptional signaling. ERD-308 is useful for studying ERα dependency, receptor degradation kinetics, transcriptional pathway suppression, ESR1-associated biology, and mechanistic differences between receptor antagonism and targeted receptor degradation.

Applications

• PROTAC-Mediated ER Degradation: ERD-308 is designed to facilitate the selective degradation of estrogen receptors (ER) in cellular models. This application is crucial for studying the role of ER in various biological pathways and can aid in elucidating mechanisms of hormone-dependent cancers.

• Targeted Protein Degradation in Oncology: Utilizing ERD-308 enables researchers to investigate the effects of targeted protein degradation in cancer cells. By specifically degrading oncogenic proteins, this PROTAC can help in understanding tumor progression and resistance mechanisms, providing valuable insights for potential therapeutic interventions.

• Mechanistic Studies of Protein Homeostasis: ERD-308 serves as a powerful tool for studying protein homeostasis by inducing the degradation of specific proteins. Researchers can explore the dynamics of protein turnover and its implications in cellular stress responses, paving the way for new discoveries in cellular biology.

• Selective Estrogen Receptor Modulation: With ERD-308, scientists can achieve selective modulation of estrogen receptor activity through targeted degradation. This application allows for detailed analysis of receptor function and interaction with co-regulators, contributing to the understanding of receptor-mediated transcriptional regulation.

1. Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)

Jiantao Hu, Biao Hu, Mingliang Wang, Fuming Xu, Bukeyan Miao, Chao-Yie Yang, Mi Wang, Zhaomin Liu, Daniel F Hayes, Krishnapriya Chinnaswamy, James Delproposto, Jeanne Stuckey, Shaomeng Wang J Med Chem. 2019 Feb 14;62(3):1420-1442. doi: 10.1021/acs.jmedchem.8b01572.Epub 2019 Jan 18.

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 DC50 (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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