7YMK

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

Summary for 7YMK

• Entry DOI: 10.2210/pdb7ymk/pdb
• Descriptor: Estrogen receptor, Grip peptide, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: complex, inhibitor, estrogen receptor alpha, transcription-inhibitor complex, transcription, transcription/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 60845.16

Authors

Min, J.,Hu, H.B.,Yang, Y.,Dong, C.E.,Zhou, H.B.,Chen, C.-C.,Guo, R.-T. (deposition date: 2022-07-28, release date: 2023-05-31, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.25 Å)