7YMK

Estrogen Receptor Alpha Ligand Binding Domain C381S C417S Y537S Mutant in Complex with an Covalent Selective Estrogen Receptor Degrader 29c and GRIP Peptide

7YMK の概要

• エントリーDOI: 10.2210/pdb7ymk/pdb
• 分子名称: Estrogen receptor, Grip peptide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: complex, inhibitor, estrogen receptor alpha, transcription-inhibitor complex, transcription, transcription/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 60845.16

構造登録者

Min, J.,Hu, H.B.,Yang, Y.,Dong, C.E.,Zhou, H.B.,Chen, C.-C.,Guo, R.-T. (登録日: 2022-07-28, 公開日: 2023-05-31, 最終更新日: 2023-12-20)

主引用文献

Wang, Y.,Min, J.,Deng, X.,Feng, T.,Hu, H.,Guo, X.,Cheng, Y.,Xie, B.,Yang, Y.,Chen, C.C.,Guo, R.T.,Dong, C.,Zhou, H.B.
Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.
Acta Pharm Sin B, 13:4963-4982, 2023

PubMed Abstract: Endocrine-resistance remains a major challenge in estrogen receptor positive (ER) breast cancer (BC) treatment and constitutively active somatic mutations in ER are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ER activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD was identified with superior anti-proliferative activity than fulvestrant against a panel of ER breast cancer cell lines including mutant ER. Crystal structure of ER‒ complex alongside intact mass spectrometry revealed that disrupted ER protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ER degradation. These significant effects of the cSERD on ER homeostasis, unlike typical ER degraders that occur directly long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). , showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

PubMed: 38045063
DOI: 10.1016/j.apsb.2023.05.005

実験手法

X-RAY DIFFRACTION (2.25 Å)