{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang Y"],"funding":["Fundamental Research Funds for the Central Universities","China Postdoctoral Science Foundation","National Natural Science Foundation of China","National Key Research and Development Program of China"],"pagination":["4963-4982"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10692362"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13(12)"],"pubmed_abstract":["Endocrine-resistance remains a major challenge in estrogen receptor <i>α</i> positive (ER<i>α</i><sup>+</sup>) breast cancer (BC) treatment and constitutively active somatic mutations in ER<i>α</i> 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<i>α</i> 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 <b>29c</b> was identified with superior anti-proliferative activity than fulvestrant against a panel of ER<i>α</i><sup>+</sup> breast cancer cell lines including mutant ER<i>α</i>. Crystal structure of ER<i>α</i>‒<b>29c</b> complex alongside intact mass spectrometry revealed that <b>29c</b> disrupted ER<i>α</i> protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ER<i>α</i> degradation. These significant effects of the cSERD on ER<i>α</i> homeostasis, unlike typical ER<i>α</i> degraders that occur directly <i>via</i> long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). <i>In vivo</i>, <b>29c</b> 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."],"journal":["Acta pharmaceutica Sinica. B"],"pubmed_title":["Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer."],"pmcid":["PMC10692362"],"funding_grant_id":["2020YFA0908800","81773557","2021YFC2100300","2042022kf0056","82173676","82103994","82273774","82073690","2020M672435"],"pubmed_authors":["Guo X","Chen CC","Guo RT","Cheng Y","Min J","Yang Y","Hu H","Feng T","Wang Y","Zhou HB","Deng X","Dong C","Xie B"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.","description":"Endocrine-resistance remains a major challenge in estrogen receptor <i>α</i> positive (ER<i>α</i><sup>+</sup>) breast cancer (BC) treatment and constitutively active somatic mutations in ER<i>α</i> 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<i>α</i> 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 <b>29c</b> was identified with superior anti-proliferative activity than fulvestrant against a panel of ER<i>α</i><sup>+</sup> breast cancer cell lines including mutant ER<i>α</i>. Crystal structure of ER<i>α</i>‒<b>29c</b> complex alongside intact mass spectrometry revealed that <b>29c</b> disrupted ER<i>α</i> protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ER<i>α</i> degradation. These significant effects of the cSERD on ER<i>α</i> homeostasis, unlike typical ER<i>α</i> degraders that occur directly <i>via</i> long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). <i>In vivo</i>, <b>29c</b> 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Dec","modification":"2026-05-28T21:35:16.879Z","creation":"2025-04-19T20:20:43.895Z"},"accession":"S-EPMC10692362","cross_references":{"pubmed":["38045063"],"doi":["10.1016/j.apsb.2023.05.005"]}}