2023
DOI: 10.1021/acs.jmedchem.3c01186
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Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

Zhixiang Chen,
Biao Hu,
Rohan Kalyan Rej
et al.

Abstract: Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability … Show more

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Cited by 17 publications
(9 citation statements)
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“…Because cereblon (CRBN) ligands have been successfully employed for the development of orally active PROTAC degraders, we focused our design of orally active PROTAC CBP/p300 degraders using cereblon ligands. In our previous studies, we have developed an optimized cereblon ligand, namely TX-16, , which has a similar binding affinity to cereblon as compared to thalidomide and lenalidomide and demonstrates favorable cell-permeability and an excellent PK profile. Using TX-16, we have successfully developed potent and orally efficacious ER and AR PROTAC degraders, which have desirable PK profiles across species. , Therefore, we employed the CRBN ligand TX-16 for the design of orally bioavailable CBP/p300 PROTAC degraders in the present study.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Because cereblon (CRBN) ligands have been successfully employed for the development of orally active PROTAC degraders, we focused our design of orally active PROTAC CBP/p300 degraders using cereblon ligands. In our previous studies, we have developed an optimized cereblon ligand, namely TX-16, , which has a similar binding affinity to cereblon as compared to thalidomide and lenalidomide and demonstrates favorable cell-permeability and an excellent PK profile. Using TX-16, we have successfully developed potent and orally efficacious ER and AR PROTAC degraders, which have desirable PK profiles across species. , Therefore, we employed the CRBN ligand TX-16 for the design of orally bioavailable CBP/p300 PROTAC degraders in the present study.…”
Section: Resultsmentioning
confidence: 99%
“…In this paper, we report our design, synthesis, and biological evaluation of a series of novel CBP/p300 PROTAC degraders based on the CBP/p300 bromodomain inhibitor, GNE-049, and a new CRBN ligand, TX-16, developed from our laboratory. , Our efforts have led to the discovery of CBPD-268 as an exceptionally potent and orally efficacious CBP/p300 degrader. CBPD-268 was capable of inducing profound degradation of CBP/p300 proteins at picomolar concentrations in cells and potently and effectively inhibited the cell growth in three AR+, advanced prostate cancer cell lines.…”
Section: Introductionmentioning
confidence: 99%
“…Therefore, given its status as one of the most developed PROTAC molecules, there is significant optimism that ARV-471 will secure FDA approval to treat a specific group of breast cancer patients. In 2023, Wang et al developed ERD-3111, an orally bioavailable estrogen receptordegrading PROTAC (Figure 13) [74]. The development of ERD-3111 is based on extensive optimization of the linker and ER inhibitor core.…”
Section: Discovery Of Orally Bioavailable Er Protac Degraders For The...mentioning
confidence: 99%
“…In an article in this issue of the Journal of Medicinal Chemistry, Shaomeng Wang and co-workers report an exceptionally potent and orally efficacious CBP and p300 PROTAC degrader for the treatment of prostate cancer with excellent PK/PD properties. 1 PCa is one of the most commonly diagnosed cancers and the leading cause of cancer mortalities in men. The androgen receptor (AR) transcriptional complex plays a key role in the progression of PCa.…”
mentioning
confidence: 99%
“…In their recent paper, Shaomeng Wang and co-workers report their work on the discovery of CBPD-268 as an exceptionally potent and orally efficacious CBP/p300 degrader. 1 In that study, they initially designed and synthesized a series of novel CBP/p300 PROTACs with various linkers based on the highly potent, selective, and cell-permeable CBP/p300 bromodomain inhibitor GNE-049 and a new CRBN ligand, TX-16. Through extensive structure−activity relationship studies, they discovered CBPD-268 as the most promising CBP/p300 degrader (Figure 1).…”
mentioning
confidence: 99%