7Y8F

Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with an Inhibitor 30o and GRIP Peptide

Summary for 7Y8F

• Entry DOI: 10.2210/pdb7y8f/pdb
• Descriptor: Estrogen receptor, Grip peptide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: complex, inhibitor, estrogen receptor alpha, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 60850.31

Authors

Min, J.,Hu, H.B.,Yang, Y.,Dong, C.E.,Zhou, H.B.,Chen, C.-C.,Guo, R.-T. (deposition date: 2022-06-23, release date: 2023-04-26, Last modification date: 2023-11-29)

Primary citation

Xin, L.,Min, J.,Hu, H.,Li, Y.,Du, C.,Xie, B.,Cheng, Y.,Deng, X.,Deng, X.,Shen, K.,Huang, J.,Chen, C.C.,Guo, R.T.,Dong, C.,Zhou, H.B.
Structure-guided identification of novel dual-targeting estrogen receptor alpha degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer.
Eur.J.Med.Chem., 253:115328-115328, 2023

PubMed Abstract: Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

PubMed: 37037140
DOI: 10.1016/j.ejmech.2023.115328

Experimental method

X-RAY DIFFRACTION (2.22 Å)